Novel heteroaryl compounds

Abstract

The invention provides new heteroaromatic compounds having the general formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, Y1, Y2, Y3, and n are as defined herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to novel compounds, particularly pyridine compounds, useful as Kv7.2 enhancers (or positive modulators), their manufacture, pharmaceutical compositions, kits comprising the compounds, and their use as medicaments for the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2. These disorders, diseases, or disabilities can be selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disability, epilepsies, neurodegenerative diseases, pain, migraine, and tinnitus.BACKGROUND OF THE INVENTION

[0002] The potassium channel family 7, or Q, contains five proteins that in humans are encoded by the genes KCNQ1, KCNQ2, KCNQ3, KCNQ4, and KCNQ5. The KCNQ proteins form homo- and hetero-tetrameric channels that respond to membrane voltage changes and open to let potassium ions flow out of cell membranes. Homomeric Kv7.2 channels as well as heteromeric Kv7.2 and Kv7.3 channels have been investigated because of their unique distribution and their potential role as primary regulators of neuronal excitability in many CNS and PNS pathways (Wang et al., 1998). KCNQ2 channels control the neuronal resting membrane potential, the spike frequency adaptation of neuronal firing, and presynaptic release. Impairment in their function leads to network instability even when lost exclusively in inhibitory neurons (Soh et al., 2018).

[0003] A significant percentage of childhood epilepsies are associated with KCNQ2 mutations (Lee et al., 2019). Human genetic studies identify de novo mutations in KCNQ2 as the third most robust link to epileptic encephalopathy (EE) (Zhao et al., 2020). Whether primary or secondary EEs, seizure activity worsens clinical outcomes and alters normal neurodevelopment (von Deimling, Helbig and Marsh, 2017). Pediatric epilepsies affect about 1 in 200 children (Waaler et al., 2000) driving cognitive, behavioral and neurological deficits (Simkin and Kiskinis, 2018). In the case of specific pathogenic KCNQ2 mutations, despite most individuals eventually becoming seizure-free, developmental delays are experienced by the majority of patients (Kato et al., 2013). Targeting Kv7 channels offers a genetically validated target against epilepsy with a differentiated mode of action amongst anti-epileptics (Gunthorpe, Large and Sankar, 2012). Kv7.2 enhancers show the potential to transform neurodevelopmental trajectories by treating the neural network instability responsible for EEs (Kessi et al., 2020).

[0004] The connection between epilepsy and autism is robust (Srivastava and Sahin, 2017) and derives from the convergent phenotypes driven by a multitude of small genetic contributors, in combination with environmental factors. KCNQ2 is one of the top 5 ion channels associated with Autism Spectrum Disorder (ASD) and one of the top 30 of all de novo mutations known in ASD (Zhao et al., 2020).

[0005] Another defining feature of ASD, Atypical Sensory Processing (ASP) (Thye et al., 2018), is also driven by convergent genetics as seen in co-twin-control studies (Neufeld et al., 2021). The biology responsible for increased sensory sensitivity has been studied in preclinical models. There, multi-sensory neuronal hyper-excitability emerges regardless of the genetic manipulation that originally drives pathological neurodevelopment. Some genes whose manipulation leads to sensory sensitivity include CNTNAP2 (Peiagarikano et al., 2011), SHANK3 (Holder and Quach, 2016) and GABRB3 (Tanaka et al., 2012). Kv7.2 enhancers show the potential to correct neurodevelopmental trajectories in ASD by normalizing network stability, neural information processing, and sensory abnormalities, ultimately responsible for atypical social and repetitive behaviors in ASD. It is also interesting that KCNQ2 knock-out mice show repetitive behaviors and aberrant exploratory and social behaviors (Kim et al., 2019).

[0006] Kv7.2 enhancers also showed promise in syndromic neurodevelopmental disorders in part because of the prevalence and impact of epilepsies (Budisteanu et al., 2020). For example, epilepsy is prevalent (>80%) in Angleman syndrome, mostly starting before 3 years of age (Fiumara et al., 2010).

[0007] Another neurodevelopmental disorder, Dup15q syndrome (Dup15q), is caused by the partial duplication of Chromosome 15 that confers a considerable risk for autism spectrum disorder, epilepsy, and intellectual disability. Dup15q patient-derived induced pluripotent cells show KCNQ2 anomalies, and Retigabine, a pan-Kv7 channel opener, partially corrects their phenotype (Fink et al., 2018). Epilepsies are central to Dup15q, with Kv7.2 enhancers showing potential to transform this neurodevelopmental disorder.

[0008] In Fragile X syndrome, about 15% of individuals experience epilepsy (Berry-Kravis, 2002) together with abnormal sensory processing (McCullagh et al., 2020). KCNQ2 (Kv7.2 gene) is downregulated in the absence of Fragile X Mental Retardation Protein (FMRP) in rodent models (Zhang et al., 2018). Therefore, Kv7.2 enhancers could positively impact Fragile X by acting on both epilepsies and sensory processing.

[0009] Infantile epilepsies are associated with intellectual disabilities, and KCNQ2 de novo mutations are significantly associated with intellectual disability (Zhao et al., 2020). Kv7.2 enhancement may address the underlying biology that exacerbates the disability.

[0010] For all these neurodevelopmental disorders, early diagnosis and the identification of the correct antiepileptic treatment is at the core of the strategies aiming at normalizing neurodevelopmental trajectories.

[0011] Within behavioral disorders, Kv7.2 enhancers showed promise in attention-deficit hyperactivity disorder (ADHD) as well as major depressive disorder (MDD, depression). Some patients with KCNQ2 mutations and mild epilepsy phenotype, show cognitive delay and ADHD (Lee et al., 2019). Kv7.2 enhancers were suggested to treat the neural network instability and the behavioral impulsivity linked to ADHD. In the MDD space, Retigabine (Kv7 opener) showed antidepressant efficacy in patients by acting on the brain's reward centers (Tan et al., 2018). The significant reduction in depressive symptoms observed with retigabine places Kv7.2 enhancers as therapeutic candidates in MDD.

[0012] The therapeutic potential of Kv7.2 enhancers in pain sensitivity is supported by the localization of Kv7.2 channels in dorsal root ganglia and their established role in pain perception (Brown and Passmore, 2009). Non-selective Kv7.2 enhancers showed efficacy in reducing the excitability of human peripheral axons (Lang et al., 2008). Retigabine has already shown some efficacy in preclinical pain models (Korsgaard et al., 2005; Xu et al., 2010; Wu et al., 2017). Retigabine also shows efficacy in controlling spreading depression, a wave of cellular depolarization associated with migraines (Aiba and Noebels, 2021).

[0013] Within sensory abnormalities, aberrant plasticity of KCNQ2 channels is strongly linked to the induction of tinnitus (Li, Choi and Tzounopoulos, 2013). This link is based on the localization of Kv7.2 channels in the cochlea (Jin et al., 2009) and how cochlear damage depends on neuronal excitability driven by the closure of Kv7.2 channels (Liu, Glowatzki and Fuchs, 2015). Retigabine prevents the development of tinnitus in preclinical models (Li, Choi and Tzounopoulos, 2013). As evidence in support of how KCNQ2 pathologies are connected between indications, it is interesting to find that tinnitus and hyperacusis are more prevalent in ASD than in the general population (Danesh et al., 2015).

[0014] In neurodegenerative diseases, dysregulated K+ homeostasis in chronic neuro-inflammatory conditions is central to disease progression. For example, in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease of the motor nervous system (Hardiman et al., 2017), diverse genetics converge onto motorneuron excitotoxicity (Kanai et al., 2006; Pasinelli and Brown, 2006) and specifically axonal hyperexcitability predicts survival (Kanai et al., 2012). Patient-derived motor neurons show membrane hyperexcitability and the tool compound Retigabine (pan-Kv7 enhancer) rescues phenotype (Wainger et al., 2014). The motorneuron hyperexcitability was found early in presymptomatic in vivo systems (Kuo et al., 2004) where it is a contributor to disease progression. Recently, clinical trials in ALS with Retigabine showed efficacy on functional biomarkers of ALS (Wainger et al., 2021) and preclinically protects against peripheral neuropathy (Nodera et al., 2011).

[0015] In Alzheimer's disease (AD), neuronal hyperexcitability and network instability (Frere and Slutsky, 2018) are early features of both IPSC models of sporadic AD (Ghatak et al., 2019), and genetic in vivo models (Palop et al., 2007; Kazim et al., 2017; Styr and Slutsky, 2018). Network instability worsens proteinopathy (Dolev et al., 2013; Frere and Slutsky, 2018) with consequences for patients (Vossel et al., 2013; Lam et al., 2017).

[0016] Because motor neuron and cortical neuron degeneration can be meaningfully slowed down by reducing aberrant neuronal activity, Kv7.2 enhancement could be an effective way to stop such aberrant activity, changing the neurodegenerative trajectory of the disease.

[0017] Therefore, enhancing the activity of Kv7.2 is a promising strategy for the treatment or prevention of diseases associated with Kv7.2. These include neurodevelopmental disorders like autism and Fragile X, epilepsy, intellectual disability, depression, attention deficit hyperactivity disorder, motor neuron excitability, pain, migraine, and sensory processing disorders.

[0018] WO2020 / 163268 relates to pyridine urea derivatives as KCNQ potentiators.

[0019] U.S. Pat. No. 5,384,330 relates to pharmacologically active 1,2,4-triaminobenzene derivatives modulating potassium ion channels Kv7.2-Kv7.5 (KCNQ2-KCNQ5) for the treatment of drug-resistant epilepsy. The compounds showed tolerability issues and other side effects.

[0020] Furthermore, the bioactivation of drugs to produce chemically reactive metabolites is an undesirable property for a drug intended for use in patients because of the observation that most drugs that cause serious idiosyncratic clinical adverse reactions form reactive metabolites capable of covalent binding to protein (Park et al., 2011). Some reactive metabolites can form adducts with glutathione (GSH) when used as trapping agent in in vitro experiments. The formation of GSH adducts in human liver microsomes can therefore provide valuable information on the potential of molecules to undergo bioactivation to reactive metabolites (Dieckhaus et al., 2005; Brink et al., 2014) and, since GSH adduct formation translates with high probability into increased levels of covalent binding to hepatic microsomal protein, GSH adduct formation could further serve as a surrogate marker for covalent binding to human hepatic protein (Evans et al., 2004). Compounds that do not to form GSH adducts when incubated in human liver microsomes under the conditions of metabolic activation in vitro may therefore be deemed to pose a low risk for reactive metabolite formation in humans (Brink et al., 2017).

[0021] To date, no agents acting on Kv7.2 are approved for the treatment of any of the diseases, disorders, or disabilities described herein, and thus there remains a need for modulators of Kv7.2 which provide a therapeutic benefit. Further, it would be beneficial to have modulators of Kv7.2 which are highly selective over other Kv7 channels. There is a need for Kv7.2 modulators which provide for a combination of favorable pharmacological properties, such as for example potency, selectivity, and metabolic stability.

[0022] It is, therefore, an object of this invention to provide selective Kv7.2 enhancers with favorable pharmacological properties useful as Kv7.2 enhancers (or positive modulators) for the therapeutic and / or prophylactic treatment of disorders, diseases, or disabilities associated with Kv7.2, and preferably demonstrating beneficial low propensity to form GSH adducts when incubated in human liver microsomes under the conditions of metabolic activation.REFERENCES

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[0042] Kanai, K. et al. (2006) “Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage,”Brain: a journal of neurology, 129(Pt 4), pp. 953-962.

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[0045] Kazim, S. F. et al. (2017) “Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer's Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP / Aβ Antibody and by mGluR5 Blockade,”Frontiers in aging neuroscience, 9, p. 71.

[0046] Kessi, M. et al. (2020) “Intellectual Disability and Potassium Channelopathies: A Systematic Review,”Frontiers in genetics, 11, p. 614.

[0047] Kim, E. C. et al. (2019) “Heterozygous loss of epilepsy gene KCNQ2 alters social, repetitive, and exploratory behaviors,”Genes, Brain and Behavior. doi: 10.1111 / gbb.12599.

[0048] Korsgaard, M. P. G. et al. (2005) “Anxiolytic effects of Maxipost (BMS-204352) and retigabine via activation of neuronal Kv7 channels,”The Journal of pharmacology and experimental therapeutics, 314(1), pp. 282-292.

[0049] Kuo, J. J. et al. (2004) “Hyperexcitability of cultured spinal motoneurons from presymptomatic ALS mice,”Journal of neurophysiology. physiology.org, 91(1), pp. 571-575.

[0050] Lam, A. D. et al. (2017) “Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease,”Nature medicine, 23(6), pp. 678-680.

[0051] Lang, P. M. et al. (2008) “Retigabine reduces the excitability of unmyelinated peripheral human axons,”Neuropharmacology, 54(8), pp. 1271-1278.

[0052] Lee, I.-C. et al. (2019) “KCNQ2 mutations in childhood nonlesional epilepsy: Variable phenotypes and a novel mutation in a case series,”Molecular genetics &genomic medicine, 7(7), p. e00816.

[0053] Li, S., Choi, V. and Tzounopoulos, T. (2013) “Pathogenic plasticity of Kv7.2 / 3 channel activity is essential for the induction of tinnitus,”Proceedings of the National Academy of Sciences of the United States of America. National Academy of Sciences, 110(24), pp. 9980-9985.

[0054] Liu, C., Glowatzki, E. and Fuchs, P. A. (2015) “Unmyelinated type II afferent neurons report cochlear damage,”Proceedings of the National Academy of Sciences of the United States of America, 112(47), pp. 14723-14727.

[0055] McCullagh, E. A. et al. (2020) “Mechanisms underlying auditory processing deficits in Fragile X syndrome,”FASEB journal: official publication of the Federation of American Societies for Experimental Biology. doi: 10.1096 / fj.201902435R.

[0056] Neufeld, J. et al. (2021) “A co-twin-control study of altered sensory processing in autism,”Autism: the international journal of research and practice, 25(5), pp. 1422-1432.

[0057] Ng, F. L et al. (2011). Expression and function of the K+ channel KCNQ genes in human arteries. British Journal of Pharmacology, 162(1), 42-53.

[0058] Nodera, H. et al. (2011) “Neuroprotective effects of Kv7 channel agonist, retigabine, for cisplatin-induced peripheral neuropathy,”Neuroscience letters, 505(3), pp. 223-227.

[0059] Palop, J. J. et al. (2007) “Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease,”Neuron, 55(5), pp. 697-711.

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[0061] Pasinelli, P. and Brown, R. H. (2006) “Molecular biology of amyotrophic lateral sclerosis: insights from genetics,”Nature reviews. Neuroscience, 7(9), pp. 710-723.

[0062] Peñagarikano, O. et al. (2011) “Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits,”Cell, 147(1), pp. 235-246.

[0063] Simkin, D. and Kiskinis, E. (2018) “Modeling Pediatric Epilepsy Through iPSC-Based Technologies,”Epilepsy currents / American Epilepsy Society, 18(4), pp. 240-245.

[0064] Soh, H. et al. (2018) “Deletion of KCNQ2 / 3 potassium channels from PV+ interneurons leads to homeostatic potentiation of excitatory transmission,”eLife, 7. doi: 10.7554 / eLife.38617.

[0065] Srivastava, S. and Sahin, M. (2017) “Autism spectrum disorder and epileptic encephalopathy: common causes, many questions,”Journal of neurodevelopmental disorders, 9, p. 23.

[0066] Styr, B. and Slutsky, I. (2018) “Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer's disease,”Nature neuroscience, 21(4), pp. 463-473.

[0067] Tan, A. et al. (2018) “Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder,”Molecular psychiatry. doi: 10.1038 / s41380-018-0283-2.

[0068] Tanaka, M. et al. (2012) “GABRB3, Epilepsy, and Neurodevelopment,” in Noebels, J. L. et al. (eds.) Jasper's Basic Mechanisms of the Epilepsies. Bethesda (MD): National Center for Biotechnology Information (US).

[0069] Thye, M. D. et al. (2018) “The impact of atypical sensory processing on social impairments in autism spectrum disorder,”Developmental cognitive neuroscience. Elsevier, 29, pp. 151-167.

[0070] Vossel, K. A. et al. (2013) “Seizures and epileptiform activity in the early stages of Alzheimer disease,”JAMA neurology, 70(9), pp. 1158-1166.

[0071] Waaler, P. E. et al. (2000) “Prevalence, classification, and severity of epilepsy in children in western Norway,”Epilepsia, 41(7), pp. 802-810.

[0072] Wainger, B. J. et al. (2014) “Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons,”Cell reports, 7(1), pp. 1-11.

[0073] Wainger, B. J. et al. (2021) “Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial,”JAA neurology, 78(2), pp. 186-196.

[0074] Wang, H. S. et al. (1998) “KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel,”Science. American Association for the Advancement of Science, 282(5395), pp. 1890-1893.

[0075] Wu, Z. et al. (2017) “Activation of KCNQ Channels Suppresses Spontaneous Activity in Dorsal Root Ganglion Neurons and Reduces Chronic Pain after Spinal Cord Injury,”Journal of neurotrauma, 34(6), pp. 1260-1270.

[0076] Xu, W. et al. (2010) “Activation of voltage-gated KCNQ / Kv7 channels by anticonvulsant retigabine attenuates mechanical allodynia of inflammatory temporomandibular joint in rats,”Molecular pain, 6, p. 49.

[0077] Zhang, F. et al. (2018) “Fragile X mental retardation protein modulates the stability of its m6A-marked messenger RNA targets,”Human molecular genetics. Oxford Academic, 27(22), pp. 3936-3950.

[0078] Zhao, G. et al. (2020) “Gene4Denovo: an integrated database and analytic platform for de novo mutations in humans,”Nucleic acids research. Oxford Academic, 48(D1), pp. D913-D926.SUMMARY OF THE INVENTION

[0079] In some aspects, provided herein is a pharmaceutical composition comprising a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof:wherein R1, R2, R3, R4, R, Y1, Y2, Y3, n and R6 are as defined herein.

[0081] In a further aspect, the present invention provides compounds of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof.

[0082] In a further aspect, the present invention provides a process for the preparation of a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof.

[0083] In a further aspect, the present invention provides a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt, when manufactured according to a process described herein.

[0084] In a further aspect, the present invention provides a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as therapeutically active substance.

[0085] In a further aspect, the present invention provides a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2.

[0086] In a further aspect, the present invention provides the use of a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2.

[0087] In a further aspect, the present invention provides the use of a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2.

[0088] In a further aspect, the present invention provides a method for the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv.2, which method comprises administering a therapeutically effective amount of a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0089] In a further aspect, the present invention provides a kit for use in the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2, comprising:

[0090] a) a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or a pharmaceutical composition for use comprising the same; and

[0091] b) instructions for use.

[0092] In a further aspect, the present invention provides the invention as hereinbefore described.

[0093] The compounds of formula (I′), or a solvate or a pharmaceutically acceptable salts thereof, as described herein, provide for a combination of favorable pharmacological properties, such as for example potency, selectivity, and metabolic stability. A reasonable metabolic stability is important to ensure a suitable pharmacological half life, which is best achieved with compounds that have a human liver microsomal clearance below 20 uL / min / mg. Selectivity within the Kv7 family is desirable to avoid actions on tissues without therapeutic potential for the indications described in this invention. For example, actions on Kv7.4 and Kv7.5 in skeletal and smooth muscle impact the function of human arteries, where KCNQ2 expression is minimal or undetected in these tissues (Ng et al 2011).

[0094] The same embodiments as described above are included for a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein R1, R2, R3, R4, R5, n and R6 are as defined herein.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0096] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any embodiments explicitly disclosed herein. Any embodiment described in this application can be combined with any other embodiment. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, and abstract), or to any novel one, or any novel combination, of the any embodiment, or any steps of any method or process so disclosed.

[0097] “Administer”, “administered”, or “administering” when used for the therapeutic and / or prophylactic treatment of disorders, diseases, or disabilities as described herein means the giving of a compound of this invention to a patient or subject by any method, e.g. by infusion, inhalation, injection, paste, suppository, or tablet. etc.

[0098] As used herein, the terms “including”, “containing”, and “comprising” are used in their open, non-limiting sense.

[0099] The articles “a” and “an” as used in this disclosure may refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” may mean one element or more than one element.

[0100] As described herein, compounds of the present disclosure may be “unsubstituted” or “substituted” with one or more substituents (e.g., 1, 2, 3, 4, or 5), such as those illustrated generally herein, or as exemplified by particular classes, subclasses, and species of the present disclosure. In general, the term “substituted” refers to the replacement of a hydrogen atom in a given structure with a specified substituent. In some embodiments, more than one hydrogen atom is replaced with a specified substituent (e.g. when two hydrogen atoms are replaced with one oxo substituent). Combinations of substituents envisioned by the present disclosure are typically those that result in the formation of stable or chemically feasible compounds. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has substituents as described herein.

[0101] As used herein, the term “unsubstituted” may mean that the specified group bears no substituents beyond the moiety recited (e.g., where valency is satisfied by hydrogen).

[0102] The terms “effective amount” or “therapeutically effective amount” refers to an amount of a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the afore-mentioned, being sufficient to produce a desired therapeutic outcome, such as reducing the severity of duration of, stabilizing the severity of, or eliminating one or more signs, symptoms or causes of a disease, disorder, or disability. For therapeutic use, beneficial or desired results may include, for example, decreasing one or more symptoms resulting from the disease, disorder, or disability (biochemical, histologic and / or behavioral), including its complications and intermediate pathological phenotypes presenting during development of the disease, disorder, or disability, increasing the quality of life of those suffering from the disease, disorder, or disability, decreasing the dose of other medications required to treat the disease, disorder, or disability, enhancing effect of another medication, delaying the progression of the disease, disorder, or disability and / or prolonging survival of patients.

[0103] The term “pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.

[0104] The term “excipient” or “pharmaceutical excipients” as used herein refers to any pharmaceutically acceptable excipient that may be used in the production of a drug or pharmaceutical composition, such as a tablet containing a compound as described herein (or tautomer or pharmaceutically acceptable salt) as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a diluent, filler, extender, binder, disintegrant, glidant, humectant, coating, emulsifier or dispersing agent, compression / encapsulation aid, cream or lotion, lubricant, solution for parenteral administration, material for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Disintegrant refers to excipients that expand and dissolve when wet causing the tablet to break apart in the body and release the active ingredient for absorption. Examples include cross-linked polymers like crospovidone, croscarmellose sodium, etc. and modified starches like sodium starch glycolate. Filler refers to excipients that fill out the size of a tablet by increasing the bulk volume. Fillers make it possible for the final product to have the proper volume for patient handling. Examples of fillers are plant cellulose, lactose, starch, mannitol, etc. Specific examples are lactose monohydrate like Pharmatose 200M, microcrystalline cellulose (MCC) like Avicel PH101, or Avicel PH102 and spray dried lactose like Fast Flo 316™. Binders refers to excipients that hold the ingredients in a tablet together. Binders ensure that tablets and granules can be formed with required mechanical strength. Examples of binders are, polyvinlypyrrolidon (PV), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), cellulose, sugar alcohols like sorbitol, proteins like gelatin and polymers like PVP, e.g. copovidone (PVP / VA 64), PEG, etc. Lubricants refer to excipients that prevent ingredients from clumping together and from sticking to the tablet punches or capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low fraction between active ingredient and wall. Examples of lubricants are minerals like talc or silica and fats like stearin, magnesium stearate, etc. Coatings may include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include e.g. calcium carbonate, dextrose, fructose dc (dc—“directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc. Creams or lotions include, e.g., maltodextrin, carrageenans, etc. Materials for chewable tablets include, e.g. dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc. Suspending / gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc. Sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc. Wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc. In some cases, the term “excipient” encompasses pharmaceutically acceptable carriers. The skilled person knows suitable pharmaceutical compositions to be used in the treatment of patients and how to produce them.

[0105] The term a “patient” or “subject” may encompass both mammals and non-mammals. Examples of mammals may include, but are not limited to, any member of the class Mammalia: humans; nonhuman primates such as chimpanzees, monkeys, baboons, or rhesus monkeys, as well as other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; companion animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. “Patient” or “subject” may include both human and animals. In some preferred embodiments, the “patient” or “subject” is a human.

[0106] As used herein, the terms “treat” or “treatment” are meant to indicate a postponement of development of one or more disease(s), disorder(s), or disability(ies); preventing the development of one or more disease(s), disorder(s), or disability(ies); and / or reducing severity of one or more symptoms of a disease, disorder, or disability that will or are expected to develop. Thus, these terms may include ameliorating one or more existing disease, disorder, or disability symptoms; preventing one or more additional symptoms; ameliorating or preventing the underlying causes of one or more symptoms; inhibiting the diseases, disorder, or disability, e.g., arresting the development of the diseases, disorder, or disability; relieving the diseases, disorder, or disability; causing regression of the diseases, disorder, or disability; relieving a symptom caused by the diseases, disorder, or disability; or stopping or alleviating the symptoms of the diseases, disorder, or disability.

[0107] Compounds of the invention and disclosure may exist as solvates. The term “solvate” may refer to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates may include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

[0108] The term “prophylaxis” as used herein includes: preventing or delaying the appearance of clinical symptoms of diseases, disorder, or disability developing in a patient or subject, especially a human, that may be afflicted with or predisposed to the disease, disorder, or disability as described herein, but does not yet experience or display clinical or subclinical symptoms of the disease, disorder, or disability.

[0109] As used herein, the term “about,” when referring to a value is meant to encompass variations of, for example, in some embodiments±20%, in some embodiments±10%, in some embodiments±5%, in some embodiments±1%, in some embodiments±0.5%, and in some embodiments±0.10% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions.

[0110] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper and lower limit of the range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these small ranges which may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0111] Numerical ranges, as used herein, may include sequential integers. For example, a range expressed as “from 0 to 5” would include 0, 1, 2, 3, 4, and 5.

[0112] A “metabolite” is a product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result e.g. from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds of the invention, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0113] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products.

[0114] The terms “compound of this invention,” and “compounds of the present invention” and “compounds or formula (I′)”, or “compounds of formula (I)” include compounds of formula (I′) or formula (I), compounds selected from any of formulae (I*), (I**), (II), (III) etc., compounds selected from tables 1-9, solvates, pharmaceutically acceptable salts, stereoisomers, geometric isomers, tautomers, metabolites, prodrugs, polymorphs; and mixtures thereof.

[0115] The symbols “*” at the end of a bond or “” drawn through a bond each refer to the point of attachment of a functional group or other chemical moiety to the rest of the molecule of which it is a part. Thus, for example:means that the substituent is attached to the rest of the molecule as shownA bond drawn into ring system (as opposed to connected at a distinct vertex) indicates that the bond may be attached to any of the suitable ring atoms.The term “optional” or “optionally” as used herein means that a subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted” means that the optionally substituted moiety may incorporate a hydrogen atom or a substituent. “Optionally substituted” means that a compound can be unsubstituted or substituted as defined herein. “Optionally substituted” means that a given substituent can be unsubstituted or further be substituted with certain substituents as defined herein and listed in the different embodiments. E.g. as a non-limiting example, the wording R6 can be cyclobutyl optionally substituted with one or two C1-6alkyl means that R6 comprises unsubstituted cyclobutyl or cyclobutyl substituted with one or two C1-6alkyl.

[0118] The term “independently” is used herein to indicate that a variable is applied in any one instance without regard to the presence or absence of a variable having that same or a different definition within the same compound. Thus, in a compound in which R″ appears twice and is defined as “independently carbon or nitrogen”, both R″s can be carbon, both R″s can be nitrogen, or one R″ can be carbon and the other nitrogen. In an addition, e.g. in a compound in which e.g. R2 and R3 are independently selected from hydrogen and hydroxyC1-6alkyl, both R2 and R3 can be hydrogen, or both can be hydroxyC1-6alkyl, or one of R2 and R3 can be hydrogen and the other one hydroxyC1-6alkyl.

[0119] In this application the units ul, uMol, C etc. mean μl, μMol, ° C. etc.

[0120] In this application, in the expression “forming a saturated monocyclic 3-5 membered cycloalkyl”, as formed by R2 / R3 and / or R4 / R5 as described herein, the “saturated monocyclic 3-5 membered cycloalkyl” means an optionally substituted cycloalkyl selected from cyclopropyl, cyclobutyl, and cyclopentyl, which are optionally substituted with halogen or haloC1-6alkyl. In particular the cycloalkyl, e.g. cyclopropyl, is unsubstituted.

[0121] In this application in the expression “forming a saturated monocyclic 3-6 membered cycloalkyl”, as formed by R2 / R3 and / or R4 / R5 as described herein, the “saturated monocyclic 3-6 membered cycloalkyl” means an optionally substituted cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, which are optionally substituted with halogen or haloC1-6alkyl. In particular, the cycloalkyl, e.g. cyclopropyl, is unsubstituted.

[0122] The term “EC50” in this application is defined as: the agonistic effect of a compound can be determined by testing the compound in an in vitro assay as described herein, whereby the effect of the compound is measured across a range of compound concentrations. The resulting data is plotted as a concentration response curve, which typically follows a sigmoidal function, whereby the concentration of the compound is plotted on the x axis and the response (agonistic effect) is plotted on the y axis. The term “EC50” is the “half maximal effective concentration” and denotes the concentration of a particular compound required to obtain 50% of the maximum response (Emax) which is observed for that compound in the given in vitro assay.

[0123] A compound of this invention may exist in one or more stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the subject matter disclosed herein. Likewise, it is understood that a compound or salt may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the subject matter disclosed herein. It is to be understood that the subject matter disclosed herein includes combinations and subsets of the particular groups described herein. The scope of the subject matter disclosed herein includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically / diastereomerically enriched mixtures. It is to be understood that the subject matter disclosed herein includes combinations and subsets of the particular groups defined herein.

[0124] A compound of this invention can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0125] According to the Cahn-Ingold-Prelog Convention, the asymmetric carbon atom can be of the “R” or “S” configuration.

[0126] The term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. Chiral separation of a racemate to its enantiomeric components may be performed to separate the eutomer and the distomer.

[0127] The term “stereoisomers” refers to compounds, which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0128] “Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as chromatography.

[0129] “Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0130] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Any organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.

[0131] The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0132] The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0133] It should be understood that individual enantiomers and diastereomers are included in the tables below by compound name, and their corresponding structures can be readily determined therefrom. In some instances, the enantiomers or diastereomers are identified by their respective properties, for example, retention times on a chiral HPLC or their biological activities (e.g., as described further in the Examples), and the absolute stereo configurations of one or more chiral centers are arbitrarily assigned (e.g., stereochemistry of all chiral centers is arbitrarily assigned, or stereochemistry of one chiral center is known and remaining chiral centers arbitrarily assigned, etc.).

[0134] In some embodiments of the invention only one of the possible enantiomers are used. In other embodiments mixtures of the possible enantiomers having different percentages for each component are used.

[0135] In some embodiments, compounds of this invention re isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (e.g., radiolabeled) compounds of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salts thereof, are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salts thereof, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. Certain isotopically-labeled compounds of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salts thereof, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of this invention can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0136] Substitution with positron emitting isotopes, such as 3H, 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of this invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0137] In one embodiment, the present invention provides pharmaceutically acceptable salts of the compounds of this invention as described herein, especially pharmaceutically acceptable salts selected from hydrochlorides, fumarates, lactates (in particular derived from L-(+)-lactic acid), tartrates (in particular derived from L-(+)-tartaric acid) and trifluoroacetates. In yet a further particular embodiment, the present invention provides compounds of this invention, as described herein (i.e., as “free bases” or “free acids”, respectively).

[0138] When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 97% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 98% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.

[0139] The term “alkyl” refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“C1-6alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2 or 3 carbon atoms. Some non-limiting examples of methyl (CH3—), ethyl (CH3CH2—), n-propyl (CH3CH2CH2—), 2-propyl (isopropyl, (CH3)2CH2—), n-butyl (CH3CH2CH2CH2—), iso-butyl ((CH3)2CH2CH2—), sec-butyl (CH3CH(CH3)CH2—), and tert-butyl ((CH3)3C—). Preferred, yet non-limiting, examples of alkyl are tert-butyl ((CH3)3C—) or methyl (CH3—). A preferred, yet non-limiting, example of alkyl is methyl (CH3—). Another preferred, yet non-limiting, example of alkyl is tert-butyl ((CH3)3C—).

[0140] The term “alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. The alkoxy group contains 1 to 6 carbon atoms (“C1-6alkoxy”), e.g. 1, 2, 3, 4, 5, or 6 carbon atoms. In other embodiments, the alkoxy group contains 1 to 4 carbon atoms. In still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include CH3O— (methoxy), CH3CH2O— (ethoxy), CH3CH2CH2O— (n-propoxy), and (CH3)3CO— (tert-butoxy). A particularly preferred, yet non-limiting, example of alkoxy is methoxy (CH3O—).

[0141] The term “C3-8cycloalkylC1-6alkoxy” as used herein refers to an alkoxy group, wherein at least one of the hydrogen atoms was replaced by a C3-8cycloalkyl group. Preferably, “C3-5cycloalkylC1-6alkoxy” refers to an alkoxy group wherein one, two, or three hydrogen atoms of the alkoxy group have been replaced by a C3-8cycloalkyl group. Preferably, “C3-8cycloalkylC1-6alkoxy” refers to an alkoxy group wherein one hydrogen atom of the alkoxy group has been replaced by a C3-8cycloalkyl group. Preferably, the alkoxy group comprises one C-atom. Preferred, yet not-limiting, examples are 2-cyclopropylmethoxy and 2-cyclobutylmethoxy.

[0142] The term “cyanoC1-6alkoxy” as used herein refers to an alkoxy group, wherein at least one of the hydrogen atoms was replaced by a cyano group. Preferably, “cyanoC1-6alkoxy” refers to an alkoxy group wherein one, two, or three hydrogen atoms of the alkoxy group have been replaced by a cyano group. Preferably, “cyanoC1-6alkoxy” refers to an alkoxy group wherein one hydrogen atom of the alkoxy group has been replaced by a cyano group. Preferably, the alkoxy group comprises one C-atom. In one embodiment, “cyanoC1-6alkoxy” is selected from NC—CH2O—, NC—CH2CH2O—, and NCCH2CH2CH2O—. In a preferred embodiment, the cyanoC1-6alkoxy is NC—CH2O—. A preferred, a yet not-limiting, example is NC—CH2O—. A preferred example is 2-cyanomethoxy with the structure NC—CH2O—.

[0143] The term “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term “halogen” or “halo” refers to fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, yet non-limiting examples of “halogen” or “halo” are fluoro (F) and chloro (Cl).

[0144] The term “cycloalkyl” as used herein refers to a monocyclic, or polycyclic, saturated or partly unsaturated, non-aromatic 3-10 membered monocyclic, or polycyclic hydrocarbon group of 3-10 ring carbon atoms (“C3-10cycloalkyl”). In a preferred embodiment, the cycloalkyl is a 4-10 membered cycloalkyl. In some embodiments, the 4-10 membered cycloalkyl groups are monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a saturated monocyclic 3-5 or a 4-6 membered hydrocarbon group of 3 to 5 or 4 to 6 ring carbon atoms, e.g., of 3, 4, or 5; or 4, 5, or 6 carbon atoms. In a preferred embodiment, the saturated monocyclic 3-6 or 4-6 membered cycloalkyl is selected from cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, cycloalkyl comprises one or two non-aromatic double bond(s). In some embodiments, cycloalkyl comprises one non-aromatic double bond. In some embodiments, cycloakyl is a monocyclic 4-6 membered cycloalkenyl group with one non-aromatic double bond. In some embodiments, cycloalkenyl is selected from cyclobutenyl, cyclopentenyl, and cyclohexenyl. Polycyclic and bicyclic cycloalkyl groups may include fused, or bridged polycyclic or bicyclic moieties, wherein each ring is a saturated or partially unsaturated, non-aromatic hydrocarbon. Cycloalkyl comprises bicyclic cycloalkyl referring to 4-10 membered bridged cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms. In some embodiments the cycloalkyl is a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings. In one preferred embodiment, cycloalkyl is selected from a 4-10 membered bridged cycloalkyl, a saturated monocyclic 3-6 or 4-6 membered cycloalkyl group, a 6 membered cycloalkenyl group, or a 7-10 membered bicycylic fused cycloalkyl. In one particularly preferred embodiment, cycloalkyl is selected from a 4-10 membered bridged cycloalkyl, a saturated monocyclic 4-6 membered cycloalkyl group, or a 7-10 membered bicycylic fused cycloalkyl. In some examples the 4-10 membered bridged cycloalkyls are selected from bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and adamantane. In some examples the 4-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings are selected from bicyclo[3.1.0]hexanyl, octahydropentalenyl, bicyclo[3.2.0]heptanyl, bicyclo[3.2.1]octanyl, bicyclo[3.2.2]octanyl, and hexahydropentalenyl. In some cases, cycloalkyl does not include bicyclic or polycyclic spiro cycloalkyl ring systems. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[3.2.1]octanyl, adamantane, bicyclo[3.2.0]heptanyl, bicyclo[3.2.1]octanyl and hexahydropentalenyl and octahydropentalene. Other examples can be found in the tables of this application.

[0145] “Heterocycloalkyl” or “heterocyclyl” as used herein refers to non-aromatic, monocyclic, or polycyclic ring systems containing carbon and at least one ring heteroatom forming a 5-12 membered heterocycloalkyl. Heterocycles are for example described in Paquette, Leo A.; “Principles of Modem Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. In some embodiments, the heterocycloalkyl is bicyclic. In some embodiments, the heteroatom is independently selected from the group consisting of N-atoms, 0-atoms, and S-atoms. In some embodiments, the heteroatom is an 0-atom. The heterocycloalkyl group may be saturated or partially unsaturated, and unless otherwise specified, may comprise 5, 6, 7, 8, 9, 10, 11, 12, or more ring atoms, where ring atoms refer to the sum of carbon and heteroatoms in the one or more rings (e.g., be a 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered, 11 membered, or 12 membered heterocycloalkyl). Heterocycloalkyl may include groups comprising 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 or 2 ring heteroatoms, or 1 ring heteroatom. In some embodiments, the 1 ring atom is an O-atom. In some embodiments the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl comprises one ring, two rings, three rings, four rings, or more, for example as a polycyclic fused system. In some embodiments, the heterocycloalkyl is a bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein one ring comprises one O-atom. In some embodiments, the heterocycloalkyl is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring or two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom, e.g. dihydrochromenyl. In some embodiments the bicyclic fused heterocycloalkyl comprises one or two non-aromatic double bond(s). In some embodiments, heterocycloalkyl comprises one non-aromatic double bond. In some embodiments, the heterocycloalkyl is a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom, e.g. cyclopenta[c]pyrrolyl having the structureor hexahydrocyclopenta[b]furan-6a-yl having e.g. the structureIn some embodiments, heterocycloalkyl comprises a 7-10 membered bridged heterosystem, wherein the bridge comprises an O-atom, e.g. oxabicyclo[2.2.1]heptanyl e.g. having the structureIn some embodiments, heterocycloalkyl is selected from bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom. In some particularly preferred embodiments heterocycloalkyl is selected from a 5-12 membered heterocycloalkyl, which heterocycloalkyl is a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom. In some cases, heterocycloalkyl does not include bicyclic or polycyclic spiro heterocycloalkyl ring systems. Preferred, but not limiting, examples of heterocycloalkyl include, oxetanyl, dihydrochromenyl, hexahydrocyclopenta[b]furanyl. Other examples can be found in the tables of this application.“Heterocyclyloxy” as used herein refers to a C1-6alkoxy group, wherein a 4-6 membered heterocycloalkyl group is linked to an —O— to form an alkoxy group. Preferably, a yet not-limiting, example is oxetanyloxy (specifically oxetan-3-yloxy).“C1-6alkyl-6 membered cycloalkenyl” as used herein refers to a C1-6alkyl group, wherein a 6 membered heterocycloalkyl group is linked to the alkyl group. Preferably, yet not-limiting, examples are“Heteroaryl” as used herein refers to a 5 or 6 membered monocyclic, aromatic group comprising at least one ring heteroatom. In some embodiments, the heteroatom is independently selected from the group consisting of N-atoms, O-atoms, and S-atoms. The number of ring atoms refer to the sum of carbon and heteroatoms in the one ring. In some embodiment, heteroaryl is a 5 or 6 membered moncyclic, aromatic group with two N-atoms. In some embodiments, heteroaryl is a 5 or 6 membered monocyclic aromatic group comprising one N-atom. In some embodiments, heteroaryl is a 5 or 6 membered monocyclic aromatic group comprising one N-atom and one 0-atom. Examples of 5 membered heteroaryl groups include, but are not limited to, pyrrolyl pyrazolyl, imidazolyl, oxazolyl, triazolyl, or furanyl. In some preferred embodiments, 5 membered heteroaryl is pyrazolyl, imidazolyl, or oxazolyl. In some more preferred embodiments, membered heteroaryl is pyrazolyl or imidazolyl. Examples of 6 membered heteroaryl groups include, but are not limited to, pyrimidinyl, pyridinyl, pyrazinyl, or pyridazinyl. In some more preferred embodiments, 6 membered heteroaryl is pyrazinyl, pyridinyl or pyrimidinyl.The term “cyano” refers to a —CN (nitrile) group.The term “oxo” refers to an=0 group.The term “hydroxy” or “hydroxyl” refers to an OH group.

[0152] The term “haloalkyl” refers to a C1-6alkyl group, with one to six C-atoms, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by one or more halogen atoms. Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, i.e. haloalkyl includes monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like. Halogen atoms may be fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred, yet non-limiting, examples of “halogen” are fluoro (F) and chloro (Cl). More preferably, haloalkyl is substituted with fluoro (F). As described above, the alkyl part can be linear or branched. Preferred, yet non-limiting, examples of haloalkyl are (CH3)2FC— (1-fluoro-isopropyl), CF3CH2— (2,2,2-trifluoroethyl), CH3CF2— (1,1-difluoroethyl), CF3— (trifluoromethyl), CH2F— (fluoromethyl), or CHF2— (difluromethyl). Particularily preferred is (CH3)2CF— (1-fluoro-isopropyl).

[0153] “Haloalkoxy”, as used herein, refers to a C1-6alkoxy group, wherein at least one of the hydrogen atoms has been replaced by halogen atoms. Preferably, “haloalkoxy” refers to an alkoxy group wherein 1, 2, or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, i.e. haloalkoxy includes monohaloalkoxy, dihaloalkoxy, trihaloalkoxy, perhaloaloxy and the like. Halogen atoms may be fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, yet non-limiting, examples of “halogen” are fluoro (F) and chloro (Cl). More preferably, haloalky is substituted with fluoro (F). The alkyl part of haloalkoxy can be linear or branched as describe above, and the haloalkoxy for example have the structure:Preferred, yet non-limiting examples of haloalkoxy are CHF2O—, CH2FO— CF3CH2O—, CF2HCH2O—, CH3CF2CH2O—, and CH3CFHCH2O—, CH3CF2CH2O—, CF3CH(CH3)O—, or FCHCH2CHFCH2O—“haloalkylthio” as used herein, refers to a thio group comprising a haloC1-6alkyl group. Preferably, “haloalkylthio” refers to an alkylthio group wherein 1, 2, or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, i.e. haloalkylthio includes monohaloalkylthio, dihaloalkylthio, trihaloalkylthio, perhaloalkylthio and the like. Halogen atoms may be fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, yet non-limiting, examples of “halogen” are fluoro (F) and chloro (Cl). More preferably, haloalky is substituted with fluoro (F). The alkyl part of haloalkylthio can be linear or branched as describe above. Preferred, yet non-limiting examples of haloalkoxy are CHF2S—, CH2FS— CF3CH2S—, CF2HCHs—, CH3CF2CH2S—, and CH3CFHCH2S—. A particularly preferred example has the structure:The term “hydroxyalkyl” refers to a C1-6alkyl group, with one to six C-atoms, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by one or more hydroxy. Preferably, “hydroxyalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by hydroxy, i.e. hydroxyalkyl includes monohydroxyalkyl, dihydroxalkyl, trihydroxyalkyl, perhydroxyalkyl and the like. More preferably, “hydroxyalkyl” refers to a C1-6alkyl group wherein one hydrogen atom has been replaced by hydroxy. The alkyl part of hydroxyalkyl can be linear or branched as describe above. Particularly preferred, yet not limiting examples of hydroxyalkyl are HOCH2— (hydroxymethyl), HOCH(CH3)—, HOCH2CH2— (hydroxyethyl), HOCH2CH2CH2— (n-hydroxypropyl) and HOCH2CH2CH2CH2— (n-hydroxybutyl).

[0156] The term “mood disorder” as used herein relates to a mental health problem that primarily affects a person's emotional state. It is a disorder in which a person experiences long periods of extreme happiness, extreme sadness or both. Two of the most common mood disorders are depression and bipolar disorder.

[0157] The term “depression” as used herein relates to a mood disorder that causes a persistent feeling of sadness and loss of interest. It is also known as major depressive disorder (MDD).

[0158] The term“behavioral disorder” relates to disorders that involve a pattern of disruptive behaviors in children that last for at least 6 months and cause problems in school, at home and in social situations. Behavioral disorders involve a pattern of disruptive behaviors in children that last for at least 6 months and cause problems in school, at home and in social situations. The most important behavioral disorder is Attention deficit hyperactivity disorder” (ADHD).

[0159] The term “Attention deficit hyperactivity disorder” (ADHD) as used herein relates to a behavioral disorder characterized by inattention, or excessive activity and impulsivity. ADHD occurs more frequently in people with epilepsy than in the general population. Children with ADHD have an increased risk of seizures, with approximately 14% of children with ADHD developing seizures.

[0160] The term “developmental disorder” or “neurodevelopmental disorder” as used herein relates to a group of conditions caused by an impairment in physical, learning, language, or behavior areas. These conditions begin during the developmental period, may impact day-to-day functioning, and can last through a person's lifetime. Examples of neurodevelopment disorders include Autism Spectrum Disorder (“ASD”) and syndromic developmental disorders.

[0161] The term “Autism Spectrum Disorder (ASD)” as used herein relates to a developmental disorder of variable severity that is characterized by difficulty in social interaction and communication and by restricted or repetitive patterns of thought and behavior. ASD encompasses mostly idiopathic but also syndromic forms and is currently diagnosed according to the diagnostic and statistical manual version 5 (DSM V).

[0162] The term “syndromic developmental disorder” as used herein relates to a development disorder with a clinically defined pattern of somatic abnormalities and a neurobehavioral phenotype that may include ASD. The diagnosis is typically confirmed by targeted genetic testing. Examples for syndromic development disorders include Dup15q syndrome (Dup15q), Fragile X syndrome (FXS) and Angelman syndrome.

[0163] The term “Dup15q syndrome” or “Duq15q” as used herein relates to the common name for chromosome 15q11.2-q13.1 duplication syndrome. This is a syndromic development disorder, caused by the partial duplication of Chromosome 15, which confers a strong risk for autism spectrum disorder, epilepsy and intellectual disability.

[0164] The term “Fragile X syndrome” (FXS) as used herein relates to a genetic disorder characterized by mild-to-moderate intellectual disability. This disorder is typically caused by an expansion of the CGG triplet repeat within the FMR1 (fragile X mental retardation 1) gene on the X chromosome.

[0165] The term “Angelman syndrome” as used herein relates to a genetic disorder that mainly affects the nervous system due to a lack of function of part of chromosome 15 inherited from a person's mother. Characteristic features of this condition include delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy).

[0166] The term “Intellectual disability” (ID) used herein relates to a generalized neurodevelopmental disorder characterized by significantly impaired intellectual and adaptive functioning. It is defined by an IQ under 70, in addition to deficits in two or more adaptive behaviors that affect everyday, general living. ID is also known as a general learning disability and formerly known as mental retardation (MR).

[0167] The term “epilepsy” used herein relates to a neurological disorder marked by sudden recurrent episodes of sensory disturbance, loss of consciousness, or convulsions, associated with abnormal electrical activity in the brain. Examples of epilepsies include broad pediatric epilepsies, West syndrome, Ohtahara syndrome and epileptic encephalopathy.

[0168] The term “neurodegenerative diseases” used herein relates to diseases that are related to e progressive loss of structure or function of neurons, including the death of neurons. Examples of neurodegenerative diseases include, but are not limited to, Alzheimer's disease and motor neuron diseases.

[0169] The term “motor neuron disease” used herein relates to a group of rare neurodegenerative disorders that selectively affect motor neurons. Examples of motor neuron diseases include, but are not limited to, amyotrophic lateral sclerosis (ALS).

[0170] The term “pain” as used herein relates to an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain including chemotherapy induced neuropathy, phantom pain and phsychogenic pain.

[0171] The term “migraine” as used herein relates to a moderate to severe headache disorder, causing throbbing or pulsating pain for hours or days.

[0172] The term “Tinnitus” as used herein relates to a symptom characterized by the perception of sound when no corresponding external sound is present.

[0173] Any disease, disorder, or disability described herein also includes any state or condition related to such disease, disorder, or disability.Compounds of the Invention

[0174] All compound names of compound structures were generated using OpenEye Lexichem, Version 1.2.0, OpenEye Scientific Software, Santa Fe, NM, USA; www.eyesopen.com.

[0175] In all embodiments of this invention providing a compound of formula (I) or formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, wherein n is 0, the respective carbon atom and the respective substituents R4 and R5 are absent.

[0176] In some embodiments of this invention providing a compound of formula (I) or formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, R2 and R3, together with the one carbon atom to which they are attached to, do not form as saturated monocyclic cycloalkyl as described herein.

[0177] In some embodiments of this invention providing a compound of formula (I) or formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, wherein n is 1, the substituents R4 or R5 cannot be hydroxy.

[0178] In all embodiments of this invention providing a compound of formula (I) or formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3, the two or three pairs of R4 / R5 can be identical or different as described herein.

[0179] The invention provides a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof:Y1 is CRa or N;

[0181] Y2 is CRb or N;

[0182] Y3 is CRc or N;

[0183] provided that only 0 or 1 of Y1, Y2 and Y3 is N and the others are CRa, CRb, or CRc;

[0184] Ra is hydrogen or halogen;

[0185] Rb is hydrogen or halogen;

[0186] Rc is hydrogen or halogen;

[0187] and wherein R1, R2, R3, R4, R5, n and R6 are as described herein, for example as in claim 1.

[0188] In one particularly preferred embodiment, the invention provides a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, wherein zero of Y1, Y2, and Y3 are N. In this embodiment Y1, Y2, and Y3 are CRa, CRb or CRc. In this embodiment the compound of formula (I′) is of formula (I) with the structure:wherein R1, R2, R3, R4, R5, n and R6 are as described herein.

[0190] In one embodiment, the invention provides a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, wherein one of Y1, Y2, or Y3 is N. In this embodiment the other ones of Y1, Y2, and Y3 are CRa, CRb or CRc.

[0191] In one embodiment, the invention provides a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, wherein only Y1 is N. In this embodiment, Y2 and Y3 are CRb or CRc.

[0192] In one embodiment, the invention provides a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, wherein only Y2 is N. In this embodiment, Y1 and Y3 are CRa or CRc.

[0193] In one embodiment, the invention provides a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof, wherein only Y3 is N. In this embodiment, Y1 and Y2 are CRa or CRb.

[0194] This invention comprises the following compounds:

[0195] All of the features and embodiments disclosed in this specification relating to Y1, Y2 and Y3 (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive.

[0196] In one embodiment, the present invention provides a compound of formula (I*), or a solvate or pharmaceutically acceptable salt thereof:wherein:

[0198] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, heterocyclyloxy, C3-5cycloalkylC1-6alkoxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0199] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0200] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0201] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, and hydroxy; or

[0202] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0203] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 4-10 membered cycloalkyl, phenyl, C1-6alkyl, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl;

[0204] n is 0, 1, 2, or 3;

[0205] R7 is halogen, and

[0206] m is 0, 1, 2, or 3.

[0207] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0209] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, haloC1-6alkylthio, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, heterocyclyloxy, C3-8cycloalkylC1-6alkoxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl; wherein the 4-6 membered cycloalkyl is optionally substituted with one, two, or three substituents independently selected from halogen; and wherein the haloC1-6alkoxy is optionally substituted with C1-6alkoxy.

[0210] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0211] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0212] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, and hydroxy; or

[0213] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0214] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, C1-6alkyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl, C2-6 alkynyl; and

[0215] n is 0, 1, 2, or 3.

[0216] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0218] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, heterocyclyloxy, C3-8cycloalkylC1-6alkoxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl; wherein the 4-6 membered cycloalkyl is optionally substituted with one, two, or three substituents independently selected from halogen; and wherein the haloC1-6alkoxy is optionally substituted with C1-6alkoxy.

[0219] R2 and are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0220] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0221] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, and hydroxy; or

[0222] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0223] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, C1-6alkyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl, C2-6 alkynyl; and

[0224] n is 0, 1, 2, or 3.

[0225] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0227] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, heterocyclyloxy, C3-8cycloalkylC1-6alkoxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0228] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0229] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0230] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, and hydroxy; or

[0231] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0232] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, C1-6alkyl-6 membered cycloalkenyl, C1-6alkyl, Si(C1-6alkyl)3, haloC1-6alkoxy and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, cycloalkenyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, haloC1-6alkoxy, cyano, hydroxy, oxo, and haloC1-6alkyl; and

[0233] n is 0, 1, 2, or 3.

[0234] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0236] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0237] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0238] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0239] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, and hydroxy; or

[0240] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0241] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0242] n is 0, 1, 2, or 3.

[0243] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0245] R1 is selected from a 4-6 membered heterocycloalkyl, haloC1-6alkoxy, haloC1-6alkylthio, a 4-6 membered heterocyclyloxy, halogen, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0246] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0247] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0248] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, and hydroxy; or

[0249] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0250] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0251] n is 0, 1, 2, or 3.

[0252] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0254] R1 is selected from a 4-6 membered heterocycloalkyl, haloC1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0255] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0256] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0257] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, and hydroxy; or

[0258] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0259] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0260] n is 0, 1, 2, or 3.

[0261] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0263] R1 is selected from a 4-6 membered heterocycloalkyl, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0264] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, haloC1-6alkyl, haloC1-6alkoxy; and hydroxyC1-6alkyl; or

[0265] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0266] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, and hydroxy; or

[0267] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0268] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0269] n is 0, 1, 2, or 3.

[0270] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0272] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, cyanOC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, heterocyclyloxy, C3-8cycloalkylC1-6alkox, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0273] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0274] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0275] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, and hydroxy, and hydroxy; or

[0276] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0277] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 4-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0278] n is 0, 1, 2, or 3;

[0279] provided that

[0280] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0282] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0283] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0284] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0285] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy and hydroxy; or

[0286] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0287] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0288] n is 0, 1, 2, or 3;

[0289] provided thatare excluded.

[0291] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0293] R1 is selected from a 4-6 membered heterocycloalkyl, haloC1-6alkoxy, haloC1-6alkylthio, a 4-6 membered heterocyclyloxy, halogen, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0294] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0295] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0296] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, and hydroxy; or

[0297] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0298] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0299] n is 0, 1, 2, or 3;

[0300] provided thatare excluded.

[0302] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0304] R1 is selected from a 4-6 membered heterocycloalkyl, a 4-6 membered heterocyclyloxy, halogen, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-5cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0305] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0306] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0307] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, and hydroxy; or

[0308] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0309] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0310] n is 0, 1, 2, or 3;

[0311] provided thatare excluded.

[0313] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0315] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0316] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0317] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0318] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, and hydroxy; or

[0319] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0320] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH2F—, CF3—, (CH3)2CF—, cyclopropyl, and CH3O—, haloC1-6alkoxy, cyano, and hydroxy; and

[0321] n is 0, 1, 2, or 3;

[0322] provided thatare excluded.

[0324] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0326] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, heterocyclyloxy, C3-8cycloalkylC1-6alkoxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0327] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0328] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0329] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, and hydroxy; or

[0330] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0331] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0332] n is 0, 1, 2, or 3;

[0333] provided thatare excluded.

[0335] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0337] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0338] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0339] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0340] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, and hydroxy; or

[0341] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0342] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0343] n is 0, 1, 2, or 3;

[0344] provided thatare excluded.

[0346] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0348] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, CHF2O—, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0349] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0350] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0351] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, and hydroxy; or

[0352] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0353] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0354] n is 0, 1, 2, or 3.

[0355] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0357] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, CHF2O—, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6aloxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0358] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0359] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0360] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy, and hydroxy; or

[0361] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0362] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, haloC1-6alkoxy, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0363] n is 0, 1, 2, or 3;

[0364] provided thatare excluded.

[0366] In some embodiments of the present invention, R2 and R3 together with the one carbon atom to which they are attached, do not form a saturated monocyclic 3-5 membered cycloalkyl.

[0367] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0369] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, cyanOC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, heterocyclyloxy, C3-8cycloalkylC1-6alkoxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0370] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0371] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, haloC1-6alkyl, haloC1-6alkoxy, and C1-6alkoxy; or

[0372] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0373] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, and haloC1-6alkoxy; wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0374] n is 0, 1, or 2.

[0375] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0377] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, heterocyclyloxy, C3-8cycloalkylC1-6alkoxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0378] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0379] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, haloC1-6alkyl, haloC1-6alkoxy, and C1-6alkoxy; or

[0380] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0381] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, Si(C1-6alkyl)3, and haloC1-6alkoxy; wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0382] n is 0 or 1.

[0383] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0385] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, haloC1-6alkylthio, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, C3-5cycloalkylC1-6alkoxy, heterocyclyloxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0386] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0387] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, haloC1-6alkyl, haloC1-6alkoxy, and C1-6alkoxy; or

[0388] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0389] R6 is selected from:

[0390] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom;

[0391] b) a 6 membered heteroaryl;

[0392] c) a 3-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[0393] d) phenyl; and

[0394] e) haloC1-6alkyl;

[0395] which bicyclic edge-to-edge fused heterocycloalkyl; bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, bicyclic edge-to-edge fused or cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0396] n is 0, 1, or 2.

[0397] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0399] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, heterocyclyloxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0400] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0401] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0402] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0403] R6 is selected from:

[0404] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom;

[0405] b) a 6 membered heteroaryl;

[0406] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[0407] d) phenyl; and

[0408] e) haloC1-6alkyl;

[0409] which bicyclic edge-to-edge fused heterocycloalkyl; bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0410] n is 0 or 1.

[0411] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0413] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, heterocyclyloxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0414] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0415] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0416] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0417] R6 is selected from:

[0418] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom;

[0419] b) a 6 membered heteroaryl;

[0420] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[0421] d) phenyl; and

[0422] e) haloC1-6alkyl;

[0423] which bicyclic edge-to-edge fused heterocycloalkyl; bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0424] n is 0, 1, or 2.

[0425] In some preferred embodiments, n is 0 or 1.

[0426] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0428] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, heterocyclyloxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0429] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0430] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0431] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0432] R6 is selected from:

[0433] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom;

[0434] b) a 6 membered heteroaryl;

[0435] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[0436] d) phenyl; and

[0437] e) haloC1-6alkyl;

[0438] which bicyclic edge-to-edge fused heterocycloalkyl; bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0439] n is 0, 1, or 2;

[0440] provided thatare excluded.

[0442] In some embodiments, n is 0 or 1.

[0443] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0445] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0446] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0447] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0448] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0449] R6 is selected from:

[0450] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom;

[0451] b) a 6 membered heteroaryl;

[0452] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[0453] d) phenyl; and

[0454] e) haloC1-6alkyl;

[0455] which bicyclic edge-to-edge fused heterocycloalkyl; bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0456] n is 0, 1, or 2.

[0457] In some preferred embodiments, n is 0 or 1.

[0458] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0460] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0461] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0462] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0463] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0464] R6 is selected from:

[0465] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom;

[0466] b) a 6 membered heteroaryl;

[0467] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[0468] d) phenyl; and

[0469] e) haloC1-6alkyl;

[0470] which bicyclic edge-to-edge fused heterocycloalkyl; bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0471] n is 0, 1, or 2;

[0472] provided thatare excluded.

[0474] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0476] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0477] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0478] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0479] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0480] R6 is selected from:

[0481] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom;

[0482] b) a 6 membered heteroaryl;

[0483] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings; which bicyclic edge-to-edge fused heterocycloalkyl; 7-10 membered bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, and hydroxyC1-6alkyl, haloC1-6alkyl; and

[0484] n is 0, 1, or 2.

[0485] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0487] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0488] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0489] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0490] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0491] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom;

[0492] b) a 6 membered heteroaryl;

[0493] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings; which bicyclic edge-to-edge fused heterocycloalkyl; 7-10 membered bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, and hydroxyC1-6alkyl, haloC1-6alkyl; and

[0494] n is 0, 1, or 2.

[0495] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0497] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0498] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0499] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0500] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0501] R6 is selected from:

[0502] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom;

[0503] b) a 6 membered heteroaryl;

[0504] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings; which bicyclic edge-to-edge fused heterocycloalkyl; bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl are optionally substituted with one or two substituents independently selected from Cl—, F—, CH3—, and CF3—; and

[0505] n is 0, 1, or 2.

[0506] In some preferred embodiments, n is 0 or 1.

[0507] In some particularly preferred embodiments, R6 is substituted with two F—.

[0508] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0510] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, heterocyclyloxy, C3-5cycloalkylC1-6alkoxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0511] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0512] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0513] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0514] R6 is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; a 7-10 membered bridged heterocycloalkyl; a saturated monocyclic 4-6 membered cycloalkyl; phenyl; a 4-10 membered bridged cycloalkyl; a 7-10 membered fused cycloalkyl; tert-butyl; (CH3)2CF—; 6 membered heteroaryl, wherein the bicyclic fused heterocyloalkyls, bridged heterocycloalkyl, saturated monocylic cycloalkyl, bridged cycloalkyl, phenyl, fused cycloalkyl, or 6 membered heteroaryl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0515] n is 0, 1, or 2;

[0516] provided thatare excluded.

[0518] In some preferred embodiments, n is 0 or 1.

[0519] In some preferred embodiments, R6 is substituted with one or two substituents independentyl selected from halogen, C1-6alkyl, and haloC1-6alkyl.

[0520] In some preferred embodiments, R6 is substituted with one or two substituents independentyl selected from Cl—, F—, CH3—, and CF3—.

[0521] In some preferred embodiments, R6 is substituted with two F—.

[0522] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0524] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0525] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0526] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0527] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0528] R6 is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; a 7-10 membered bridged heterocycloalkyl; a saturated monocyclic 4-6 membered cycloalkyl; phenyl; a 4-10 membered bridged cycloalkyl; a 7-10 membered fused cycloalkyl; tert-butyl; (CH3)2CF—; and 6 membered heteroaryl, wherein the bicyclic fused heterocyloalkyl, bridged heterocycloalkyl, saturated monocylic cycloalkyl, bridged cycloalkyl, phenyl, fused cycloalkyl, or 6 membered heteroaryl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0529] n is 0, 1, or 2;

[0530] provided thatare excluded.

[0532] In some embodiments, n is 0 or 1.

[0533] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0535] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, CHF2O—, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0536] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0537] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0538] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0539] R6 is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; a 7-10 membered bridged heterocycloalkyl; a saturated monocyclic 4-6 membered cycloalkyl; phenyl; a 4-10 membered bridged cycloalkyl; a 7-10 membered fused cycloalkyl; tert-butyl; (CH3)2CF—; 6 membered heteroaryl, wherein the bicyclic fused heterocyloalkyl, bridged heterocycloalkyl, saturated monocylic cycloalkyl, bridged cycloalkyl, phenyl, fused cycloalkyl, or heteroaryl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0540] n is 0, 1, or 2;

[0541] provided thatare excluded.

[0543] In some embodiments, n is 0 or 1.

[0544] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0546] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, CHF2O—, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0547] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl;

[0548] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0549] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0550] R6 is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; a 7-10 membered bridged heterocycloalkyl; a saturated monocyclic 4-6 membered cycloalkyl; phenyl; a 4-10 membered bridged cycloalkyl; a 7-10 membered fused cycloalkyl; tert-butyl; (CH3)2CF—; 6 membered heteroaryl, wherein the bicyclic fused heterocyloalkyl, bridged heterocycloalkyl, saturated monocylic cycloalkyl, bridged cycloalkyl, phenyl, fused cycloalkyl, or heteroaryl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0551] n is 0, 1, or 2;

[0552] provided thatare excluded.

[0554] In some embodiments, n is 0 or 1.

[0555] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof.wherein:

[0557] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, heterocyclyloxy, C3-5cycloalkylC1-6alkoxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0558] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl; or

[0559] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0560] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0561] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0562] R6 is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyridinyl, and pyrimidinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyridinyl, or pyrimidinyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0563] n is 0, 1, or 2.

[0564] In some preferred embodiments, n is 0 or 1.

[0565] In some embodiments R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl.

[0566] In some preferred embodiments, R6 is substituted with one or two substituents independentyl selected from halogen, C1-6alkyl, and haloC1-6alkyl.

[0567] In some preferred embodiments, R6 is substituted with one or two substituents independentyl selected from Cl—, F—, CH3—, and CF3—.

[0568] In some preferred embodiment, R6 is substituted with two F—.

[0569] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0571] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl; wherein the heterocycloalkyl, heterocyclyloxy, C3-5cycloalkylC1-6alkoxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0572] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl; or

[0573] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0574] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0575] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0576] R6 is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyridinyl, and pyrimidinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyridinyl, or pyrimidinyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0577] n is 0, 1, or 2;

[0578] provided thatare excluded.

[0580] In some embodiments, n is 0 or 1.

[0581] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0583] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, or cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0584] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl; or

[0585] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0586] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0587] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0588] R6 is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, hydroxy, and haloC1-6alkyl; and

[0589] n is 0, 1, or 2;

[0590] provided thatare excluded.

[0592] In some embodiments, n is 0 or 1.

[0593] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0595] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl, wherein the heterocycloalkyl, heterocyclyloxy, C3-5cycloalkylC1-6alkoxy, or heteroaryl are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0596] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl; or

[0597] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0598] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0599] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0600] R6 is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0601] n is 0, 1, or 2;

[0602] provided thatare excluded.

[0604] In some embodiments, n is 0 or 1.

[0605] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof.wherein:

[0607] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy; wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0608] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl; or

[0609] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0610] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0611] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0612] R6 is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0613] n is 0, 1, or 2;

[0614] provided thatare excluded.

[0616] In some embodiments, n is 0 or 1.

[0617] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0619] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, CHF2O—, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy, wherein the heterocycloalkyl, C3-8cycloalkylC1-6alkoxy, or heterocyclyloxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl;

[0620] R2 and R3 are independently selected from hydrogen, C1-6alkyl, and hydroxyC1-6alkyl, and hydroxy; or

[0621] R2 and R3, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0622] R4 and R5 are independently selected from hydrogen, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, and C1-6alkoxy; or

[0623] R4 and R5, together with the one carbon atom to which they are attached, form a saturated monocyclic 3-5 membered cycloalkyl;

[0624] R6 is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0625] n is 0, 1, or 2;

[0626] provided thatare excluded.

[0628] In some embodiments, n is 0 or 1.

[0629] In one embodiment the present invention provides a compound of formula (I) or a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or solvate or pharmaceutically acceptable salt thereof:wherein:

[0631] R1 is haloC1-6alkoxy;

[0632] R2 and R3 are hydrogen;

[0633] R4 and R5 are independently selected from hydrogen, haloC1-6alkyl;

[0634] R6 is selected from a 3-10 membered cycloalkyl and a haloC1-6alkyl;

[0635] n is 1.

[0636] In one embodiment the present invention provides a compound of formula (I) or a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or solvate or pharmaceutically acceptable salt thereof:wherein:

[0638] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl; wherein the heterocycloalkyl, heterocyclyloxy, and heteroaryl are optionally substituted with one C1-6alkyl, or haloC1-6alkyl;

[0639] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0640] R2 and R3 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;

[0641] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, and hydroxy; or

[0642] R4 and R5 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;

[0643] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 4-10 membered cycloalkyl, phenyl, C1-6alkyl, and haloC1-6alkyl; wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0644] n is 0, 1, 2, or 3,

[0645] or a pharmaceutical composition comprising a compound selected from the following list or a solvate or a pharmaceutically acceptable salt thereof:ExampleNameStructure 661-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(3- ethynylcyclobutyl) urea1731-(2,2- difluorocyclopropyl)- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea2031-(3- chlorophenyl)-3- [[2-(2,2,2- trifluoroethoxy) pyrimidin-4- yl]methyl]urea2041-[[2-(2,2,2- trifluoroethoxy) pyrimidin-4- yl]methyl]-3- [(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea2091-[[2-(3,3- difluorocyclobutyl) oxypyridin-4- yl]methyl]-3- [(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea2121-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(2- trimethylsilylethyl) urea2151-[6-(2,2,2- trifluoroethoxy) pyridazin-4- yl]methyl]-3- [(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea2241-[[2-(3,3- difluorocyclobutyl) oxypyridin-4- yl]methyl]-3-(3- fluoro-1- bicyclo[1.1.1] pentanyl)urea2281-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- (1,1,1,3,3,3- hexafluoropropan- 2-yl)urea2301-[(1R)-1-(3,3- difluorocyclobutyl)- 2,2- difluoroethyl]-3- [[2- (difluoromethoxy) pyridin-4- yl]methyl]urea2521-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- [3,3,3-trifluoro-2- (trifluoromethyl) propyl]urea2531-(dicyclo- propylmethyl)- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea2601-[[2-(difluoro- methylsulfanyl) pyridin-4- yl]methyl]-3- [(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea2621-[3- (difluoromethoxy) phenyl]-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea2641-[3- (difluoromethoxy) cyclopentyl]-3- [[2- (difluoromethoxy) pyridin-4- yl]methyl]urea2651-[(1s,3s)-3- (difluoromethoxy) cyclobutyl]-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea2661-[(1r,4r)-4- (difluoromethoxy) cyclohexyl]-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea2671-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[3- (trifluoromethoxy) cyclobutyl]urea2681-[2- (difluoromethoxy) propyl]-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea2731-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- [(2S)-1,1,1,4,4,4- hexafluorobutan- 2-yl]urea2791-[[6-(2,2,2- trifluoroethoxy) pyrimidin-4- yl]methyl]-3- [(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea2811-[[2-(1,1,1- trifluoro-3- methoxypropan-2- yl)oxypyridin-4- yl]methyl]-3-[3- (trifluoromethyl) cyclobutyl]urea2821-[[6- (difluoromethoxy) pyrimidin-4- yl]methyl]-3- [(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea2851-(1,1,1,3,3,3- hexafluoropropan- 2-yl)-3-[[2-(2,2,2- trifluoroethoxy) pyridin-4- yl]methyl]urea2881-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- [(1R,3S)-3- (trifluoromethoxy) cyclopentyl]urea2941-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- [(2R)-1,1,1,4,4,4- hexafluorobutan- 2-yl]urea

[0646] In one embodiment the present invention provides a compound of formula (I′) or a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or solvate or pharmaceutically acceptable salt thereof:wherein:

[0648] Y1, Y2 and Y3 are each independently selected from CH or N;

[0649] provided that only 0 or 1 of Y1, Y2 and Y3 is N;

[0650] R1 haloC1-6alkoxy, haloC1-6 alkylthio, 4-6 membered cycloalkyloxy, wherein the 4-6 membered cycloalkyloxy is optionally substituted with one, two, or three substituents independently selected from halogen; wherein the haloC1-6alkoxy is optionally substituted with C1-6alkoxy;

[0651] R2 and R3 are independently selected from hydrogen;

[0652] R4 and R5 are independently selected from hydrogen, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, and haloC1-6alkyl;

[0653] R6 is selected from a 3-10 membered cycloalkyl, phenyl, haloC1-6alkyl, haloC1-6alkoxy, and triC1-6alkylsilyl; wherein the cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, haloC1-6alkoxy, and haloC1-6alkyl, C2-6 alkynyl; and

[0654] n is 0, 1 or 2.

[0655] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0657] R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl; wherein the heterocycloalkyl, heterocyclyloxy, and heteroaryl are optionally substituted with one C1-6alkyl, or haloC1-6alkyl;

[0658] R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; or

[0659] R2 and R3 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;

[0660] R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl, and hydroxy; or

[0661] R4 and R5 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;

[0662] R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 4-10 membered cycloalkyl, phenyl, C1-6alkyl, and haloC1-6alkyl; wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl and haloC1-6alkyl; and

[0663] n is 0, 1, 2, or 3.

[0664] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R1 is selected from cyano, haloC1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy; wherein the heterocyclyloxy or cyloalkylalkoxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl.

[0665] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R1 is selected from cyano, haloC1-6alkoxy, and haloC1-6alkyl.

[0666] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R1 is selected from cyano, CHF2O—, CH3CF2O—, CH3CFHCH2O—, CF3CH2O—, CH3CF2—, CHF2—, and CF3—.

[0667] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R1 is selected from CHF2O—, CH3CF2O—, CH3CFHCH2O—, and CF3CH2O—.

[0668] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R1 is CHF2O— or CH3CF2O—.

[0669] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein RV is CHF2O—.

[0670] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R1 is 5 membered heteroaryl selected from pyrazolyl and imidazolyl which are optionally substituted with one, two, or three substituents independently selected from halogen and haloC1-6alkyl.

[0671] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R1 is unsubstituted pyrazolyl or unsubstituted imidazolyl.

[0672] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein (i) both R2 and R3 are hydrogen, or (ii) one of R2 and R3 is hydrogen and the other one is hydroxyC1-6alkyl.

[0673] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein one of R2 and R3 is hydrogen and the other one is hydroxyC1-6alkyl selected from HOCH2—, HOCH2CH2—, HOCH2CH2CH2—, and HOCH2CH2CH2CH2—.

[0674] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein the hydroxyC1-6alkyl is HOCH2— or HOCH2CH2—.

[0675] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein both R2 and R3 are hydrogen.

[0676] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein n is 0 or 1.

[0677] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein n is 0.

[0678] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein n is 1.

[0679] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein n is 1 and (i) both R4 and R5 are hydrogen, (ii) one of R4 and R5 is hydrogen and the other one is C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, or C1-6alkoxy.

[0680] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein one of R4 and R5 is hydrogen and the other one is a methyl (CH3—) or methoxy (CH3O—).

[0681] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein the saturated monocyclic 3-5 membered cycloalkyl is unsubstituted cyclopropyl.

[0682] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein n is 1 and both R4 and R5 are hydrogen.

[0683] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R4 and R5, together with the one carbon atom to which they are attached, form cyclopropyl.

[0684] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 4-10 membered cycloalkyl, C1-6alkyl, haloC1-6alkyl, and phenyl; wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[0685] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, and a 4-10 membered cycloalkyl; wherein the heterocycloalkyl, heteroaryl, or cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[0686] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R6 is optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH2F—, CF3—, (CH3)2CF—, cyclopropyl, and CH3O—, cyano, and hydroxy.

[0687] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R6 is optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CF3—, cyclopropyl, and CH3O—.

[0688] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R6 is optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, and CF3—.

[0689] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R6 is selected from:

[0690] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom;

[0691] b) a 6 membered heteroaryl;

[0692] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[0693] d) phenyl;

[0694] e) C1-6alkyl; and

[0695] e) haloC1-6alkyl;

[0696] which are optionally substituted as described herein.

[0697] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R6 is selected from:

[0698] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom;

[0699] b) a 6 membered heteroaryl;

[0700] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[0701] which are optionally substituted as described herein.

[0702] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R6 is selected from:

[0703] dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, which are optionally substituted as described herein.

[0704] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R6 is selected from:

[0705] dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, which are optionally substituted as described herein.

[0706] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R6 is selected from:

[0707] Some particularly preferred embodiments comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, where R6 is as described herein substituted with one or two F— and wherein R6 is selected from:

[0708] Some particularly preferred embodiments comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, where R6 is as described herein substituted with one or two F— and wherein R6 is selected from:

[0709] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R is selected from CHF2O—, unsubstituted pyrazolyl, unsubstituted imidazolyl, CH3O—, (CH3)CF2—, CN—, CHF2—, CF3—, CF3CH2O—, CH3CFHCH2O—, R2 and R3 are hydrogen, n is 0 or 1, (i) R4 and R5 are hydrogen, or (ii) one of R4 and R5 are hydrogen and the other is cyclopropyl, or (iii) R4 and R5 together with the one carbon atom to which they are attached, form cyclopropyl, and R6 is selected from a 5-12 membered heterocycloalkyl which heterocycloalkyl is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom, a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom, a 7-10 membered bridged heterosystem, wherein the bridge comprises an O-atom, a 6 membered heteroaryl; and a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings, all optionally substituted as described herein.

[0710] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R1 is selected from CHF2O— or unsubstituted imidazolyl, R2 and R3 are hydrogen, n is 0 or 1, (i) R4 and R5 are hydrogen, or (ii) one of R4 and R5 are hydrogen and the other is cyclopropyl, or (iii) R4 and R5 together with the one carbon atom to which they are attached, form cyclopropyl, and R6 is selected from a 5-12 membered heterocycloalkyl which heterocycloalkyl is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom, a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom, a 7-10 membered bridged heterosystem, wherein the bridge comprises an O-atom, a 6 membered heteroaryl; and a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings, all optionally substituted as described herein.

[0711] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 37, wherein R1 is selected from CHF2O— or unsubstituted imidazolyl, R2 and R3 are hydrogen, n is 0; and R6 is selected from a 5-12 membered heterocycloalkyl which heterocycloalkyl is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom, a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom, a 7-10 membered bridged heterosystem, wherein the bridge comprises an O-atom; a 6 membered heteroaryl; and a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings, all optionally substituted as described herein.

[0712] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R1 is CHF2O— and R6 is optionally substituted with one or two Cl—, F—, CH3—, and CF3—

[0713] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R1 is CHF2O— and R6 is optionally substituted with one or two F— or CF3—.

[0714] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R1 is CHF2O—, n is 0 or 1, and R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, and a 4-10 membered cycloalkyl; wherein the heterocycloalkyl, heteroaryl, or cycloalkyl are optionally substituted with one or two F— or CF3—.

[0715] Some of the preferred embodiments of this invention comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, as described herein, wherein R1 is CHF2O—, n is 0 or 1, and R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, and a 4-10 membered cycloalkyl; wherein the heterocycloalkyl, heteroaryl, or cycloalkyl are optionally substituted with one or two CF3—.

[0716] Some of the preferred embodiments comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CHF2O— or unsubstituted imidazolyl, R2 and R3 are hydrogen, n is 0; and R6 is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; a 7-membered bridged heterocycloalkyl; a saturated monocyclic 4-6 membered cycloalkyl; phenyl; a 4-10 membered bridged cycloalkyl; a 7-10 membered fused cycloalkyl; tert-butyl; (CH3)2CF—; pyrazinyl, pyrimidinyl, and pyridinyl, wherein the bicyclic fused heterocyloalkyls, bridged heterocycloalkyl, saturated monocylic cycloalkyl, bridged cycloalkyl, phenyl, fused cycloalkyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one CF3—.

[0717] In some preferred embodiments R6 is substituted with one CF3— and one other substituent of R6 as described herein.

[0718] In some preferred embodiments, the other substituent of R6 is hydroxy and R6 has the structure:

[0719] Some particularly preferred embodiments comprise a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, where R6 is as described herein substituted with one CF3—, and wherein R6 is selected from:

[0720] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0722] R1 is selected from cyano, haloC1-6alkoxy, C1-6alkoxy, haloC1-6alkyl and 5 membered unsubstituted heteroaryl;

[0723] R2 and R3 are hydrogen;

[0724] R4 and R5 are hydrogen;

[0725] R6 is selected from a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom, a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom, a 4-10 membered bridged cycloalkyl, a saturated monocyclic 4-6 membered cycloalkyl, phenyl, (CH3)2CF—, and 6 membered heteroaryl, wherein the bicyclic fused heterocycloalkyl, bridged cycloalkyl, cycloalkyl, phenyl, or heteroaryl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0726] n is 0 or 1.

[0727] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0729] R1 is selected from cyano, haloC1-6alkoxy, C1-6alkoxy, haloC1-6alkyl and 5 membered unsubstituted heteroaryl;

[0730] R2 and R3 are hydrogen;

[0731] R4 and R5 are hydrogen;

[0732] R6 is selected from a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom, a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom, a 4-10 membered bridged cycloalkyl, a saturated monocyclic 4-6 membered cycloalkyl, phenyl, 6 membered heteroaryl, wherein the bicyclic fused heterocycloalkyl, bridged cycloalkyl, cycloalkyl, phenyl, or heteroaryl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0733] n is 0 or 1.

[0734] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0736] R1 is selected from cyano, haloC1-6alkoxy, C1-6alkoxy, haloC1-6alkyl and 5 membered unsubstituted heteroaryl;

[0737] R2 and R3 are hydrogen; or

[0738] R4 and R5 are hydrogen;

[0739] R6 is selected from a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; a 4-10 membered bridged cycloalkyl; a saturated monocyclic 4-6 membered cycloalkyl, phenyl; (CH3)2CF—; and 6 membered heteroaryl; wherein the bicyclic fused heterocycloalkyl; bridged cycloalkyl; cycloalkyl; phenyl; or heteroaryl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0740] n is 0 or 1;

[0741] provided thatare excluded.

[0743] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0745] R1 is selected from cyano, haloC1-6alkoxy, C1-6alkoxy, halo1-6alkyl and 5 membered unsubstituted heteroaryl;

[0746] R2 and R3 are hydrogen;

[0747] R4 and R5 are hydrogen;

[0748] R6 is selected from a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; a 4-10 membered bridged cycloalkyl; a saturated monocyclic 4-6 membered cycloalkyl, phenyl; (CH3)2CF—; and 6 membered heteroaryl; wherein the bicyclic fused heterocycloalkyl; bridged cycloalkyl; cycloalkyl; phenyl; or heteroaryl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; and

[0749] n is 0 or 1;

[0750] provided thatare excluded.

[0752] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0754] R1 is selected from cyano, haloC1-6alkoxy, C1-6alkoxy, haloC1-6alkyl and 5 membered unsubstituted heteroaryl;

[0755] R2 and R3 are hydrogen;

[0756] R4 and R5 are hydrogen;

[0757] R6 is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH2F—, CF3—, (CH3)2CF—, cyclopropyl, and CH3O—, cyano, and hydroxy; and

[0758] n is 0, or 1;

[0759] provided thatare excluded.

[0761] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0763] R1 is selected from cyano, CHF2O—, CH3CF2—, CH3O—, CH3CFHCH2O—, CF3CH2O—, CH3CF2—, CHF2—, CF3—, unsubstituted pyrazolyl, and unsubstituted imidazolyl;

[0764] R2 and R3 are hydrogen;

[0765] R4 and R5 are hydrogen; or

[0766] R4 and R5, together with the one carbon atom to which they are attached, form unsubstituted cyclopropyl;

[0767] R6 is selected from a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; a 4-10 membered bridged cycloalkyl; a saturated monocyclic 4-6 membered cycloalkyl, phenyl; (CH3)2CF—; pyrazinyl, pyrimidinyl, and pyridinyl; wherein the bicyclic fused heterocycloalkyl; bridged cycloalkyl; cycloalkyl; phenyl; pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH2F—, CF3—, (CH3)2CF—, cyclopropyl, and CH3O—, cyano, and hydroxy; and

[0768] n is 0, or 1;

[0769] provided thatare excluded

[0771] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0773] R1 is selected from cyano, CHF2O—, CH3CF2—, CH3O—, CH3CFHCH2O—, CF3CH2O—, CH3CF2—, CHF2—, CF3—, unsubstituted pyrazolyl, and unsubstituted imidazolyl;

[0774] R2 and R3 are hydrogen;

[0775] R4 and R5 are hydrogen; or

[0776] R4 and R5, together with the one carbon atom to which they are attached, form unsubstituted cyclopropyl;

[0777] R6 is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH2F—, CF3—, (CH3)2CF—, cyclopropyl, and CH3O—, cyano, and hydroxy; and

[0778] n is 0, or 1;

[0779] provided that

[0780] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof.wherein:

[0782] R1 is selected from CHF2O—, CH3CF2O—, CH3CFHCH2O—, CF3CH2O—, pyrazolyl, and imidazolyl; wherein the pyrazolyl and imidazolyl are unsubstituted or optionally substituted with one CF3—;

[0783] R2 and R3 are hydrogen;

[0784] R4 and R5 are hydrogen; or

[0785] R4 and R5, together with the one carbon atom to which they are attached form unsubstituted cyclopropyl;

[0786] R6 is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH2F—, CF3—, (CH3)2CF—, cyclopropyl, and CH3O—, cyano, and hydroxy; and

[0787] n is 0, or 1;

[0788] provided thatare excluded.

[0790] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0792] R1 is selected from CHF2O—, CH3CF2O—, CH3CFHCH2O—, and CF3CH2O—;

[0793] R2 and R3 are hydrogen;

[0794] R4 and R5 are hydrogen; or

[0795] R4 and R5, together with the one carbon atom to which they are attached, form unsubstituted cyclopropyl;

[0796] R6 is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH2F—, CF3—, (CH3)2CF—, cyclopropyl, and CH3O—, cyano, and hydroxy; and

[0797] n is 0, or 1.

[0798] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0800] R1 is selected from CHF2O—, CH3CF2O—, CH3CFHCH2O—, and CF3CH2O—;

[0801] R2 and R3 are hydrogen;

[0802] R4 and R5 are hydrogen; or

[0803] R4 and R5, together with the one carbon atom to which they are attached, form unsubstituted cyclopropyl;

[0804] R6 is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH2F—, CF3—, (CH3)2CF—, cyclopropyl, and CH3O—, cyano, and hydroxy; and

[0805] n is 0, or 1;

[0806] provided thatare excluded.

[0808] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0810] R1 is CHF2O— or unsubstituted imidazolyl;

[0811] R2 and R3 are hydrogen;

[0812] R4 and R5 are hydrogen; or

[0813] R4 and R5, together with the one carbon atom to which they are attached, form unsubstituted cyclopropyl;

[0814] R6 is selected from bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexenyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, and pyridinyl wherein the bicyclo[1.1.1]pentanyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH2F—, CF3—, (CH3)2CF—, cyclopropyl, and CH3O—, cyano, and hydroxy; and

[0815] n is 0, or 1.

[0816] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0818] R1 is CHF2O— or unsubstituted imidazolyl;

[0819] R2 and R3 are hydrogen;

[0820] R4 and R5 are hydrogen; or

[0821] R4 and R5, together with the one carbon atom to which they are attached, form unsubstituted cyclopropyl;

[0822] R6 is selected from bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexenyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, and pyridinyl wherein the bicyclo[1.1.1]pentanyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH2F—, CF3—, (CH3)2CF—, cyclopropyl, and CH3O—, cyano, and hydroxy; and

[0823] n is 0, or 1;

[0824] provided thatare excluded.

[0826] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0828] R1 is CHF2O—;

[0829] R2 and R3 are hydrogen;

[0830] R4 and R5 are hydrogen; or

[0831] R4 and R5, together with the one carbon atom to which they are attached, form unsubstituted cyclopropyl;

[0832] R6 is selected from bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexenyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, and pyridinyl wherein the bicyclo[1.1.1]pentanyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from C Cl—, F—, CH3—, CH2F—, CF3—, (CH3)2CF—, cyclopropyl, and CH3O—, cyano, and hydroxy; and

[0833] n is 0, or 1.

[0834] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0836] R1 is CHF2O—;

[0837] R2 and R3 are hydrogen;

[0838] R4 and R5 are hydrogen; or

[0839] R4 and R5, together with the one carbon atom to which they are attached, form unsubstituted cyclopropyl;

[0840] R6 is selected from bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexenyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the bicyclo[1.1.1]pentanyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, and CF3—; and

[0841] n is 0, or 1.

[0842] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0844] R1 is unsubstituted imidazolyl or imidazolyl substituted with one substituent selected from CH3CF2—, CF3—, CH2F, and CHF2—;

[0845] R2 and R3 are hydrogen;

[0846] R4 and R5 are hydrogen; or

[0847] R4 and R5, together with the one carbon atom to which they are attached, form unsubstituted cyclopropyl;

[0848] R6 is selected from bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexenyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, and pyridinyl wherein the bicyclo[1.1.1]pentanyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, and CF3—; and

[0849] n is 0, or 1;

[0850] provided thatare excluded.

[0852] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0854] R1 is CHF2O— or unsubstituted imidazolyl;

[0855] R2 and R3 are hydrogen;

[0856] R4 and R5 are hydrogen;

[0857] R6 is selected from bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexenyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, and pyridinyl wherein the bicyclo[1.1.1]pentanyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, and CF3—; and

[0858] n is 0, or 1.

[0859] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0861] R1 is CHF2O— or unsubstituted imidazolyl;

[0862] R2 and R3 are hydrogen;

[0863] R4 and R5 are hydrogen;

[0864] R6 is selected from bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexenyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, and pyridinyl wherein the bicyclo[1.1.1]pentanyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, and CF3—; and

[0865] n is 0, or 1;

[0866] provided thatare excluded.

[0868] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0870] R1 is CHF2O—;

[0871] R2 and R3 are hydrogen;

[0872] R4 and R5 are hydrogen;

[0873] R6 is selected from bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexenyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, and pyridinyl wherein the bicyclo[1.1.1]pentanyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, and CF3—; and

[0874] n is 0, or 1.

[0875] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0877] R1 is CHF2O—;

[0878] R2 and R3 are hydrogen;

[0879] R4 and R5 are hydrogen;

[0880] R6 is selected from bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexenyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, and pyridinyl wherein the bicyclo[1.1.1]pentanyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, and CF3—; and

[0881] n is 0, or 1.

[0882] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:

[0884] R1 is unsubstituted imidazolyl or imidazolyl substituted with one substituent selected from CH3CF2—, CF3—, CH2F, and CHF2—;

[0885] R2 and R3 are hydrogen;

[0886] R4 and R5 are hydrogen;

[0887] R6 is selected from bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexenyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, pyrazinyl, pyrimidinyl, and pyridinyl wherein the bicyclo[1.1.1]pentanyl, cyclopentyl, cyclohexyl, cyclobutyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, and bicyclo[2.2.2]octanyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, and CF3—; and

[0888] n is 0, or 1;

[0889] provided thatare excluded.

[0891] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any embodiments described herein. Any embodiment described in this application can be combined with any other embodiment. For example, any embodiment herein relating to the compounds of formula (I), or a solvate or pharmaceutically acceptable salts thereof can be combined with any embodiment of pharmaceutical compostions, kits, medical use, or method of treatment. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0892] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a 5 membered heteroaryl.

[0893] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a 5 membered heteroaryl, which is a 5 membered monocyclic, aromatic group with two N-atoms.

[0894] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a 5 membered heteroaryl, which is a 5 membered monocyclic, aromatic group comprising one N-atom and one O-atom.

[0895] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is 5 membered heteroaryl, and R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 4-10 membered cycloalkyl, phenyl, C1-6alkyl, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[0896] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is 5 membered heteroaryl, and R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, and a 4-10 membered cycloalkyl, wherein the heterocycloalkyl, heteroaryl, or cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[0897] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is 5 membered heteroaryl, and R6 is selected from:

[0898] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom; b) a 6 membered heteroaryl;

[0899] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[0900] d) phenyl;

[0901] e) C1-6alkyl; and

[0902] f) haloC1-6alkyl;

[0903] wherein the bicyclic edge-to-edge fused heterocycloalkyl, bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, cycloalkenyl, bridged cycloalkyl, bicyclic edge-to-edge fused cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[0904] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is 5 membered heteroaryl, and R6 is selected from:

[0905] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an 0-atom;

[0906] b) a 6 membered heteroaryl;

[0907] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[0908] wherein the bicyclic edge-to-edge fused heterocycloalkyl; bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[0909] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a 5 membered heteroaryl, and R6 is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH3CH2—, CF3—, cyclopropyl, CH3O—, cyano, and hydroxy.

[0910] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a 5 membered heteroaryl, and R6 is selected from dihydrochromenyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH3CH2—, CF3—, cyclopropyl, CH3O—, cyano, and hydroxy.

[0911] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein the 5 membered heteroaryl is selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, triazolyl, and furanyl.

[0912] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein the 5 membered heteroaryl is selected from pyrazolyl, imidazolyl, and oxazolyl.

[0913] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein the 5 membered heteroaryl is selected from pyrazolyl or imidazolyl, which pyrazolyl or imidazolyl are optionally substituted with one, two, or three substituents independently selected from C1-6alkyl or haloC1-6alkyl.

[0914] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein the 5 membered heteroaryl is selected from pyrazolyl and imidazolyl, which pyrazolyl or imidazolyl are optionally substituted with one C1-6alkyl or haloC1-6alkyl.

[0915] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is unsubstituted pyrazolyl.

[0916] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from pyrazolyl and imidazolyl substituted with one, two, or three haloC1-6alkyl.

[0917] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl substituted with one haloC1-6alkyl selected from (CH3)2CF—, CH3CF2—, CF3—, CH2F—, and CHF2—.

[0918] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl substituted with one CF3—.

[0919] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl substituted with one C1-6alkyl.

[0920] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl substituted with one C1-6alkyl selected from CH3—, ethyl, propyl, 2-propyl (isopropyl), n-butyl, sec-butyl, and tert-butyl.

[0921] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl substituted with one CH3—.

[0922] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl substituted with one, two, or three C1-6alkyl or haloC1-6alkyl.

[0923] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is unsubstituted imidazolyl.

[0924] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl substituted with one haloC1-6alkyl.

[0925] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl substituted with one haloC1-6alkyl selected from (CH3)2CF—, CH3CF2—, CF3—, CH2F—, and CHF2—.

[0926] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl substituted with one CF3—.

[0927] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl substituted with one C1-6alkyl.

[0928] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl substituted with one C1-6alkyl selected from CH3—, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, and tert-butyl.

[0929] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl substituted with one CH3—.

[0930] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is oxazolyl optionally substituted with one, two, or three C1-6alkyl or haloC1-6alkyl.

[0931] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is unsubstituted oxazolyl.

[0932] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is oxazolyl substituted with one haloC1-6alkyl.

[0933] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is oxazolyl substituted with one haloC1-6alkyl selected from (CH3)2CF—, CH3CF2—, CF3—, CH2F—, and CHF2—.

[0934] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is oxazolyl substituted with one CF3—.

[0935] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is oxazolyl substituted with one C1-6alkyl.

[0936] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is oxazolyl substituted with one C1-6alkyl selected from CH3—, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, and tert-butyl.

[0937] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is oxazolyl substituted with one CH3—.

[0938] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl, imidazolyl, or oxazolyl, which pyrazolyl, imidazolyl, or oxazolyl are unsubstituted or substituted as described herein, and R2 and R3 are hydrogen.

[0939] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from pyrazolyl, imidazolyl, and oxazolyl, which pyrazolyl, imidazolyl, or oxazolyl are unsubstituted or substituted as described herein, R2 and R3 are hydrogen, and n is 0, 1 or 2.

[0940] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from pyrazolyl, imidazolyl, and oxazolyl, which pyrazolyl, imidazolyl, or oxazolyl are unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, 1 or 2, and R6 is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one 0-atom, a saturated monocyclic 4-6 membered cycloalkyl, phenyl, or a 4-10 membered bridged cycloalkyl, which fused heterocycloalkyl, saturated monocyclic cycloalkyl, phenyl, or bridged cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[0941] In the embodiments wherein n is 1 or 2, R4 and R5 are hydrogen.

[0942] In some preferred embodiments, n is 0 or 1.

[0943] In some embodiments the compound of formula (I) is not:

[0944] In some embodiments the above compound is not excluded for any medical use, kits, or pharmaceutical compositions.

[0945] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl or imidazolyl, which pyrazolyl or imidazolyl are unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom, a saturated monocyclic 4-6 membered cycloalkyl, phenyl, or a 4-10 membered bridged cycloalkyl, which fused heterocycloalkyl, saturated monocyclic cycloalkyl, or bridged cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[0946] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl, which bridged cycloalkyl is optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[0947] In some embodiments of the compound of formula (I), wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl, which bridged cycloalkyl is optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl the compound is not:

[0948] In some embodiments the above compounds are not excluded for any medical use, kits, or pharmaceutical compositions.

[0949] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl and haloC1-6alkyl.

[0950] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is an unsubstituted 4-10 membered bridged cycloalkyl.

[0951] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is unsubstituted bicyclo[2.2.1]heptanyl.

[0952] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, n, R2, R3, R4, R5, and R6 are as described herein, and and non-limiting examples are selected from:

[0953] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, 1, or 2, and R6 is a monocyclic 4-6 membered cycloalkenyl group with one non-aromatic double bond, which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[0954] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, 1, or 2, and R6 is an unsubstituted monocyclic 4-6 membered cycloalkenyl group with one non-aromatic double bond.

[0955] In some embodiments wherein n is 1 or 2, R4 and R5 are both hydrogen.

[0956] In some preferred embodiments n is 0 or 1.

[0957] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 2, R4 and R5 are hydrogen, and R6 is a monocyclic 4-6 membered cycloalkenyl group with one non-aromatic double bond which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[0958] In some embodiments wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 2, R4 and R5 are hydrogen, and R6 is a monocyclic 4-6 membered cycloalkenyl group with one non-aromatic double bond the compound of formula (I) is not.

[0959] In some embodiments the above compounds are not excluded for any medical use, kits, or pharmaceutical compositions.

[0960] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 2, R4 and R5 are hydrogen, and R6 is an unsubstituted monocyclic 4-6 membered cycloalkenyl group selected from cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0961] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 2, R4 and R5 are hydrogen, and R6 is unsubstituted cyclohexenyl.

[0962] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, n, R2, R3, R4, R5, and R6 are as described herein, and a non-limiting example has the structure:

[0963] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, 1, or 2, and R6 is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom, which fused heterocycloalkyl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[0964] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, 1, or 2, and R6 is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom, which fused heterocycloalkyl is unsubstituted or substituted with one, two, or three halogen or haloC1-6alkyl.

[0965] In some embodiments, wherein n is 1 or 2, R4 and R5 are hydrogen.

[0966] In some preferred embodiments, n is 0 or 1.

[0967] In some other embodiments, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, 1, or 2, and R6 is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom, which fused heterocycloalkyl is unsubstituted or substituted with one, two, or three halogen, or haloC1-6alkyl, wherein the compound is not:

[0968] In some embodiments the above compound is not excluded for any medical use, kits, or pharmaceutical compositions.

[0969] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom, which fused heterocycloalkyl is unsubstituted or substituted with one, two, or three halogen or haloC1-6alkyl.

[0970] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom, which fused heterocycloalkyl is unsubstituted or substituted with one halogen or haloC1-6alkyl.

[0971] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom, which fused heterocycloalkyl is optionally substituted with one Cl—, F—, CH3—, and CF3—.

[0972] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is an unsubstituted bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring wherein one ring comprises one O-atom.

[0973] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is unsubstituted dihydrochromenyl.

[0974] In one more preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is

[0975] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, n, R2, R3, R4, R5, and R6 are as described herein, and a non-limiting example has the structure:

[0976] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, 1, or 2, and R6 is a 4-10 membered bridged cycloalkyl, which bridged cycloalkyl is optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[0977] In some embodiments, wherein n is 1 or 2, R4 and R5 are hydrogen.

[0978] In some preferred embodiments, n is 0 or 1.

[0979] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl, which bridged cycloalkyl is optionally substituted with one, two, or three substituents independentyl selected from halogen, C1-6 alkyl, and haloC1-6alkyl.

[0980] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl, which bridged cycloalkyl is optionally substituted with one halogen, C1-6 alkyl, and haloC1-6alkyl.

[0981] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl, which bridged cycloalkyl is unsubstituted or substituted with one Cl—, F—, CH3—, and CF3—

[0982] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is selected from unsubstituted bicyclo[1.1.1]pentanyl and bicyclo[2.2.1]heptanyl.

[0983] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is unsubstituted bicyclo[1.1.1]pentanyl.

[0984] In one more preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is

[0985] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, n, R2, R3, R4, R5, and R6 are as described herein, and non-limiting examples have the structures:

[0986] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, 1, or 2, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocyclic 4-6 membered cycloalkyl is optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[0987] In some embodiments, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, 1, or 2, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocyclic 4-6 membered cycloalkyl is optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl, wherein the compound is not;

[0988] In some embodiments the above compound is not excluded for any medical use, kits, or pharmaceutical compositions.

[0989] In some embodiments, wherein n is 1 or 2, R4 and R5 are hydrogen.

[0990] In some preferred embodiments, n is 0 or 1.

[0991] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocyclic 4-6 membered cycloalkyl optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, and haloC1-6alkyl.

[0992] In some embodiments, the saturated monocyclic 4-6 membered cycloalkyl is unsubstituted.

[0993] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which cycloalkyl is unsubstituted or substituted with one C1-6 alkyl selected from CH3—, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, and tert-butyl.

[0994] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which cycloalkyl is unsubstituted or substituted with one CH3—.

[0995] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is selected from cyclobutyl, cyclopentyl, and cyclohexyl, which cyclobutyl, cyclopentyl, or cyclohexyl are unsubstituted or substituted with one CH3—.

[0996] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is selected from unsubstituted cyclobutyl, cyclopentyl, and cyclohexyl.

[0997] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is unsubstituted cyclobutyl or unsubstituted cyclopentyl.

[0998] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is unsubstituted cyclopentyl.

[0999] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, n, R2, R3, R4, R5, and R6 are as described herein, and a non-limiting example has the structure:

[1000] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, 1, or 2, and R6 is phenyl which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1001] In some embodiments, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, 1, or 2, and R6 is phenyl which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, haloC1-6alkyl, and haloC1-6alkyl, wherein the compound is not:

[1002] In some embodiments the above compound is not excluded for any medical use, kits, or pharmaceutical compositions.

[1003] In some embodiments, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, 1, or 2, and R6 is phenyl which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, haloC1-6alkyl, and haloC1-6alkyl, only for embodiments relating to medical use, kits, or pharmaceutical compositions.

[1004] In some embodiments, wherein n is 1 or 2, R4 and R5 are hydrogen.

[1005] In some preferred embodiments, n is 0 or 1.

[1006] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is phenyl unsubstituted or substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, and haloC1-6alkyl.

[1007] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is phenyl unsubstituted or substituted with one substituent selected from halogen, C1-6 alkyl, and haloC1-6alkyl.

[1008] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is phenyl substituted with one halogen.

[1009] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is phenyl substituted with one halogen selected from F—, Cl— or Br—.

[1010] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is phenyl substituted with one Cl—.

[1011] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is pyrazolyl which is unsubstituted or substituted as described herein, n, R2, R3, R4, R5, and R6 are as described herein, and a non-limiting example has the structure:

[1012] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, 1, or 2, R4 and R5 are hydrogen, and R6 is a saturated monocyclic 4-6 membered cycloalkyl or a 4-10 membered bridged cycloalkyl, which saturated monocyclic cycloalkyl or bridged cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1013] In some embodiments, wherein n is 1 or 2, R4 and R5 are hydrogen.

[1014] In some preferred embodiments, n is 0 or 1.

[1015] In some embodiments, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, 1, or 2, R4 and R5 are hydrogen, and R6 is a saturated monocyclic 4-6 membered cycloalkyl or a 4-10 membered bridged cycloalkyl, which saturated monocyclic cycloalkyl or bridged cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl, which compound is not selected from:

[1016] In some embodiments, the compound is not excluded for any medical use, kits, or pharmaceutical compositions.

[1017] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0 or 1, R4 and R5 are hydrogen, and R6 is a saturated monocyclic 4-6 membered cycloalkyl or a 4-10 membered bridged cycloalkyl, which saturated monocyclic cycloalkyl or bridged cycloalkyl are unsubstituted or substituted with one, two, or three substituents independently selected from halogen, C3-6cycloalkyl, C1-6 alkyl, and haloC1-6alkyl.

[1018] In one more preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocyclic cycloalkyl is unsubstituted or substituted with one C3-6cycloalkyl.

[1019] In one more preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocyclic cycloalkyl is unsubstituted or substituted with one C3-6cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[1020] In one more preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocyclic cycloalkyl is unsubstituted or substituted with one cyclopropyl.

[1021] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is cyclohexyl substituted with one cyclopropyl.

[1022] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is

[1023] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, n, R2, R3, R4, R5, and R6 are as described herein, and a non-limiting example has the structure:

[1024] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocylic cycloalkyl is unsubstituted or substituted with one, two, or three C1-6alkyl.

[1025] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocyclic cycloalkyl is unsubstituted or substituted with three C1-6alkyl.

[1026] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocyclic cycloalkyl is unsubstituted or substituted with three C1-6alkyl selected from CH3—, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, and tert-butyl.

[1027] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocyclic cycloalkyl is unsubstituted or substituted with three CH3—.

[1028] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is selected from cyclobutyl, cyclopentyl, and cyclohexyl which are substituted with two or three CH3—.

[1029] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is cyclohexyl substituted with two or three CH3—.

[1030] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is cyclohexyl substituted with two or three CH3—, and one or two hydroxy.

[1031] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl which is unsubstituted or substituted as described, R2 and R3 are hydrogen, n is 0, and R6 is selected from:

[1032] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, R1 is imidazolyl, which is unsubstituted or substituted as described herein, n, R2, R3, R4, R5, and R6 are as described herein, and non-limiting examples have the structure:

[1033] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl, which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl, or a saturated monocyclic 4-6 membered cycloalkyl, which are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1034] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidzolyl, which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is an unsubstituted 4-10 membered bridged cycloalkyl.

[1035] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidazolyl, which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is unsubstituted bicyclo[2.2.1]heptanyl.

[1036] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is imidzolyl, which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl which is substituted by three substituents independently selected from Cl—, F—, CH3—, CH2F—, CF3—, (CH3)2CF—, cyclopropyl, and CH3O—, cyano, and hydroxy.

[1037] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, R1 is imidazolyl which is substituted or substituted as described herein, n, R2, R3, R4, R5, and R6 are as described herein, and a non-limiting example has the structure:

[1038] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is oxazolyl, which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl, which bridged cycloalkyl is optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1039] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is oxazolyl, which is unsubstituted or substituted as described herein, R2 and R3 are hydrogen, n is 0, and R6 is an unsubstituted 4-10 membered bridged cycloalkyl.

[1040] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is oxazolyl, which is substituted with one haloC1-6alkyl as described herein, R2 and R3 are hydrogen, n is 0, and R6 is unsubstituted bicyclo[2.2.1]heptanyl.

[1041] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, R1 is oxazolyl which is substituted or substituted as described herein, n, R2, R3, R4, R5, and R6 are as described herein, and a non-limiting example has the structure:

[1042] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from pyrazolyl, imidazolyl, and oxazolyl, which are unsubstituted or substituted as described herein, n, R2, R3, R4 and R5 are as described herein, and R6 is selected from:

[1043] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from pyrazolyl, imidazolyl, and oxazolyl, which are unsubstituted or substituted as described herein, n, R2, R3, R4 and R5 are as described herein, and R6 is selected from:

[1044] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from pyrazolyl, imidazolyl, and oxazolyl, which are unsubstituted or substituted as described herein, n, R2, R3, R4 and R5 are as described herein, and R6 is selected from:

[1045] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from pyrazolyl, imidazolyl, or oxazolyl, which are unsubstituted or substituted as described herein, n, R2, R3, R4 and R5 are as described herein, and R6 is selected from:

[1046] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from pyrazolyl, imidazolyl, and oxazolyl, which are unsubstituted or substituted as described herein, n, R2, R3, R4 and R5 are as described herein, and R6 is selected from:

[1047] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from pyrazolyl, imidazolyl, and oxazolyl, which are unsubstituted or substituted as described herein, n, R2, R3, R4 and R5 are as described herein, and R6 is selected from:

[1048] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a 5 membered heteroaryl selected from pyrazolyl, imidazolyl and oxazolyl, which are unsubstituted or substituted as described herein, n, R2, R3, R4, R5, and R6 are as described herein, and non-limiting examples are selected from:

[1049] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a haloC1-6alkyl.

[1050] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a haloC1-6alkyl, and R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 4-10 membered cycloalkyl, phenyl, C1-6alkyl, and haloC1-6alkyl; wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1051] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a haloC1-6alkyl, and R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, and a 4-10 membered cycloalkyl; wherein the heterocycloalkyl, heteroaryl, or cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1052] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a haloC1-6alkyl, and R6 is selected from:

[1053] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an 0-atom;

[1054] b) a 6 membered heteroaryl;

[1055] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[1056] d) phenyl;

[1057] e) C1-6alkyl, and

[1058] e) haloC1-6alkyl;

[1059] wherein the bicyclic edge-to-edge fused heterocycloalkyl, bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, cycloalkenyl, bridged cycloalkyl, bicyclic edge-to-edge fused cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1060] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a haloC1-6alkyl, and R6 is selected from:

[1061] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an 0-atom;

[1062] b) a 6 membered heteroaryl;

[1063] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[1064] wherein the bicyclic edge-to-edge fused heterocycloalkyl, bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, cycloalkenyl, bridged cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1065] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a haloC1-6alkyl, and R6 is selected from is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH3CH2—, CF3—, cyclopropyl, CH3O—, cyano, and hydroxy.

[1066] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a haloC1-6alkyl, and R6 is selected from is selected from dihydrochromenyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH2F—, CF3—, (CH3)2CF—, cyclopropyl, and CH3O—, cyano, and hydroxy.

[1067] In some embodiments, wherein R1 is a haloC1-6alkyl, the compound of formula (I) is not selected from.

[1068] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a haloC1-6alkyl selected from (CH3)2CF—, CF3CH2—, CH3CF2—, CF3—, CH2F—, or CHF2—.

[1069] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CHF2—, CF3—, CF3CH2—, and CH3CF2—.

[1070] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CH3CF2—.

[1071] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CF3CH2—,

[1072] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CF3—.

[1073] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CHF2—.

[1074] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from (CH3)2CF—, CF3CH2—, CH3CF2—, CF3—, CH2F—, and CHF2—, R2 and R3 are hydrogen, n is 0, 1 or 2, and R6 is a 4-10 membered bridged cycloalkyl, or a saturated monocyclic 4-6 membered cycloalkyl, wherein the bridged cycloalkyl, or saturated monocyclic cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1075] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from (CH3)2CF—, CF3CH2—, CH3CF2—, CF3—, CH2F—, and CHF2—, R2 and R3 are hydrogen, n is 0, 1 or 2, and R6 is a 4-10 membered bridged cycloalkyl, or a saturated monocyclic 4-6 membered cycloalkyl, wherein the bridged cycloalkyl, or saturated monocyclic cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6alkyl, and haloC1-6alkyl.

[1076] In some embodiments, when n is 1 or 2, R4 and R5 are hydrogen.

[1077] In some embodiments n is 0 or 1.

[1078] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from (CH3)2CF—, CF3CH2—, CH3CF2—, CF3—, CH2F—, or CHF2—, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl, or a saturated monocyclic 4-6 membered cycloalkyl, wherein the bridged cycloalkyl, or saturated monocyclic cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6alkyl, and haloC1-6alkyl.

[1079] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CF3—, CHF2—, CF3CH2—, and CH3CF2—, R2 and R3 are hydrogen, n is 0, and R6 is an unsubstituted 4-10 membered bridged cycloalkyl.

[1080] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CF3—, CHF2—, CF3CH2—, and CH3CF2—, R2 and R3 are hydrogen, n is 0, and R6 is selected from an unsubstituted bicyclo[1.1.1]pentanyl and bicyclo[2.2.1]heptanyl.

[1081] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CF3—, CHF2—, CF3CH2—, and CH3CF2—, R2 and R3 are hydrogen, n is 0, and R6 is an unsubstituted bicyclo[2.2.1]heptanyl.

[1082] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CF3—, CHF2—, CF3CH2—, and CH3CF2—, R2 and R3 are hydrogen, n is 0, and R6 is selected from bicyclo[1.1.1]pentanyl and bicyclo[2.2.1]heptanyl, which are substituted with one or two halogen, C1-6 alkyl, and haloC1-6alkyl.

[1083] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CF3—, CHF2—, CF3CH2—, and CH3CF2—, R2 and R3 are hydrogen, n is 0, and R6 is bicyclo[1.1.1]pentanyl and bicyclo[2.2.1]heptanyl, which are substituted with one or two F— or CF3—.

[1084] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CF3—, CHF2—, CF3CH2—, and CH3CF2—, R2 and R3 are hydrogen, n is 0, and R6 is an unsubstituted bicyclo[2.2.1]heptanyl.

[1085] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CF3—, CHF2—, CF3CH2—, and CH3CF2—, R2 and R3 are hydrogen, n is 0, and R6 is bicyclo[1.1.1]pentanyl and bicyclo[2.2.1]heptanyl, which are substituted with one for two F— or CF3—.

[1086] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a haloC1-6alkyl, n, R2, R3, R4, R5, and R6 are as described herein, and non-limiting examples are selected from:

[1087] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CF3—, CHF2—, CF3CH2—, and CH3CF2—, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocyclic cycloalkyl is optionally substituted with one, two, or three halogen, C1-6 alkyl, and haloC1-6alkyl.

[1088] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CF3—, CHF2—, CF3CH2—, and CH3CF2—, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocyclic cycloalkyl is optionally substituted with one haloC1-6alkyl.

[1089] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CF3—, CHF2—, CF3CH2—, and CH3CF2—, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl selected from cyclobutyl, cyclopentyl, and cyclohexyl, which cyclobutyl, cyclopentyl, or cyclohexyl are substituted with one haloC1-6alkyl.

[1090] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CF3—, CHF2—, CF3CH2—, and CH3CF2—, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl selected from cyclobutyl, cyclopentyl, and cyclohexyl, which cyclobutyl, cyclopentyl, or cyclohexyl are substituted with one haloC1-6alkyl selected from (CH3)2CF—, CF3CH2—, CH3CF2—, CF3—, CH2F—, and CHF2—.

[1091] In one more preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CF3—, CHF2—, CF3CH2—, and CH3CF2—, R2 and R3 are hydrogen, n is 0, and R6 is is a saturated monocyclic 4-6 membered cycloalkyl selected from cyclobutyl, cyclopentyl, and cyclohexyl, which cyclobutyl, cyclopentyl, or cyclohexyl are substituted with one CF3—.

[1092] In one more preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CF3—, R2 and R3 are hydrogen, n is 0, and R6 is cyclobutyl substituted with one CF3—.

[1093] In one more preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is selected from CF3—, CHF2—, CF3CH2—, and CH3CF2—, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl selected from unsubstituted cyclobutyl, cyclopentyl, and cyclohexyl.

[1094] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a haloC1-6alkyl, n, R2, R3, R4, R5, and R6 are as described herein, and non-limiting examples are selected from:

[1095] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CF3—, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl having the structure:

[1096] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CF3—, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl having the structure:

[1097] In one particularly preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a haloC1-6alkyl, n, R2, R3, R4, R5, and R6 are as described herein, and a non-limiting example has the structure:

[1098] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt, thereof, wherein R1 is a haloC1-6alkyl, n, R1, R2, R3, R4, R5, and R6 are as described herein, and non-limiting examples are selected from:

[1099] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano.

[1100] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, and R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 4-10 membered cycloalkyl, phenyl, C1-6alkyl, and haloC1-6alkyl; wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1101] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, and R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, and a 4-10 membered cycloalkyl; wherein the heterocycloalkyl, heteroaryl, or cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1102] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, and R6 is selected from:

[1103] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom;

[1104] b) a 6 membered heteroaryl;

[1105] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[1106] d) phenyl;

[1107] e) C1-6alkyl; and

[1108] f) haloC1-6alkyl;

[1109] wherein the bicyclic edge-to-edge fused heterocycloalkyl, bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, cycloalkenyl, bridged cycloalkyl, bicyclic edge-to-edge fused cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1110] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, and R6 is selected from:

[1111] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an O-atom;

[1112] b) a 6 membered heteroaryl;

[1113] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[1114] wherein the bicyclic edge-to-edge fused heterocycloalkyl; bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1115] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, and is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH3CH2—, CF3—, cyclopropyl, CH3O—, cyano, and hydroxy.

[1116] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, and R6 is selected from dihydrochromenyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH3CH2—, CF3—, cyclopropyl, CH3O—, cyano, and hydroxy.

[1117] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, and R2 and R3 are hydrogen.

[1118] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, and n is 0, 1, or 2.

[1119] In some embodiments, when n is 1 or 2, R4 and R5 are hydrogen.

[1120] In some embodiments is 0 or 1.

[1121] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, and n is 0.

[1122] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl, or a saturated monocyclic 4-6 membered cycloalkyl, which bridged cycloalkyl or saturated monocyclic cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1123] In some embodiments of the compound of formula (I), wherein R1 is cyano, R2 and R3 are hydrogen n is 0, and R6 is a 4-10 membered bridged cycloalkyl, or a saturated monocyclic 4-6 membered cycloalkyl, which bridged cycloalkyl or saturated monocyclic cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl, and the compound is not.

[1124] In some embodiments, the above compound is not excluded for any medical use, kits, or pharmaceutical compositions.

[1125] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl, or a saturated monocyclic 4-6 membered cycloalkyl, which bridged cycloalkyl or saturated monocyclic cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, or haloC1-6alkyl.

[1126] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl, or a saturated monocyclic 4-6 membered cycloalkyl, which bridged cycloalkyl or saturated monocyclic cycloalkyl are optionally substituted with one, two, or three C1-6 alkyl.

[1127] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl or a saturated monocyclic 4-6 membered cycloalkyl, which bridged cycloalkyl or saturated monocyclic cycloalkyl are optionally substituted with three C1-6 alkyl.

[1128] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocyclic cycloalkyl is optionally substituted with three C1-6 alkyl selected from CH3—, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, and tert-butyl.

[1129] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocyclic cycloalkyl are optionally substituted with three C1-6 alkyl.

[1130] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl selected from cyclobutyl, cyclopentyl, and cyclohexyl, which cyclobutyl, cyclopentyl, or cyclohexyl are optionally substituted with three CH3—.

[1131] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is cyclohexyl, which cyclohexyl is substituted with three CH3—.

[1132] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, n, R2, R3, R4, R5, and R6 are as described herein, and a non-limiting example is:

[1133] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl which is optionally substituted with one, two or three substituents independently selected from halogen, C1-6 alkyl, and haloC1-6alkyl.

[1134] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl selected from bicyclo[1.1.1]pentanyl and bicyclo[2.2.1]heptanyl which are optionally substituted with one, two or three substituents independently selected from halogen, C1-6 alkyl, and haloC1-6alkyl.

[1135] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is an unsubstituted 4-10 membered bridged cycloalkyl.

[1136] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is selected from unsubstituted bicyclo[1.1.1]pentanyl and bicyclo[2.2.1]heptanyl.

[1137] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is an unsubstituted bicyclo[2.2.1]heptanyl.

[1138] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, n, R2, R3, R4, R5, and R6 are as described herein, and a non-limiting example is:

[1139] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl or a saturated monocyclic 4-6 membered cycloalkyl which are optionally substituted as described herein, and wherein non-limiting examples of the structures of R6 are:

[1140] In one preferred embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, R2 and R3 are hydrogen, n is 0, and R6 is an unsubmitted 4-10 membered bridged cycloalkyl or a saturated monocyclic 4-6 membered cycloalkyl which is substituted with three CH3—, and wherein non-limiting examples of the structures of R6 are:

[1141] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyano, n, R2, R3, R4, R5, and R6 are as described herein, and non-limiting examples are selected from:

[1142] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a cyanoC1-6alkoxy.

[1143] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a cyanoC1-6alkoxy, and R6 is selected from is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 4-10 membered cycloalkyl, phenyl, C1-6alkyl, and haloC1-6alkyl; wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1144] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a cyanoC1-6alkoxy, and R6 is selected from is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, and a 4-10 membered cycloalkyl; wherein the heterocycloalkyl, heteroaryl, or cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1145] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a cyanoC1-6alkoxy, and R6 is selected from:

[1146] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an 0-atom;

[1147] b) a 6 membered heteroaryl;

[1148] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[1149] d) phenyl;

[1150] e) C1-6alkyl; and

[1151] f) haloC1-6alkyl;

[1152] wherein the bicyclic edge-to-edge fused heterocycloalkyl, bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, cycloalkenyl, bridged cycloalkyl, bicyclic edge-to-edge fused cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1153] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a cyanoC1-6alkoxy, and R6 is selected from:

[1154] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an 0-atom;

[1155] b) a 6 membered heteroaryl;

[1156] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[1157] wherein the bicyclic edge-to-edge fused heterocycloalkyl; bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1158] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a cyanoC1-6alkoxy, and R6 is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH3CH2—, CF3—, cyclopropyl, CH3O—, cyano, and hydroxy.

[1159] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a cyanoC1-6alkoxy, and R6 is selected from dihydrochromenyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH3CH2—, CF3—, cyclopropyl, CH3O—, cyano, and hydroxy.

[1160] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a cyanoC1-6alkoxy and R2 and R3 are hydrogen.

[1161] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a cyanoC1-6alkoxy, R2 and R3 are hydrogen and n is 0, 1, or 2.

[1162] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a cyanoC1-6alkoxy, R2 and R3 are hydrogen and n is 0.

[1163] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyanoC1-6alkoxy, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl, which saturated monocyclic cycloalkyl is optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6 alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1164] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyanoC1-6alkoxy, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl which saturated monocyclic cycloalkyl is optionally substituted with substituent selected from halogen, C1-6 alkyl, and haloC1-6alkyl as defined herein.

[1165] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyanoC1-6alkoxy, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl which saturated monocyclic cycloalkyl is optionally substituted with one substituent selected from halogen, C1-6 alkyl, and haloC1-6alkyl as defined herein.

[1166] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyanoC1-6alkoxy, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl selected from cyclobutyl, cyclopentyl, and cyclohexyl, which cyclobutyl, cyclopentyl, or cyclohexyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6alkyl, and haloC1-6alkyl.

[1167] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is a cyanoC1-6alkoxy selected from NC—CH2O—, NC—CH2CH2O—, and NCCH2CH2CH2O—.

[1168] In a preferred embodiment, the cyanoC1-6alkoxy is NC—CH2O—.

[1169] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is NC—CH2O—, R2 and R3 are hydrogen, n is 0, and R6 is cyclobutyl substituted with one haloC1-6alkyl.

[1170] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is NC—CH2O—, R2 and R3 are hydrogen, n is 0, and R6 is cyclobutyl substituted with one CF3—.

[1171] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is NC—CH2O—, R2 and R3 are hydrogen, n is 0, and R6 has the structure:

[1172] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is NC—CH2O—, R2 and R3 are hydrogen, n is 0, and R6 has the structure:

[1173] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is cyanoC1-6alkoxy, n, R2, R3, R4, R5, and R6 are as described herein, and a non-limiting example has the structure:

[1174] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy.

[1175] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, and R6 is selected from is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 4-10 membered cycloalkyl, phenyl, C1-6alkyl, and haloC1-6alkyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1176] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, and R6 is selected from is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, and a 4-10 membered cycloalkyl, wherein the heterocycloalkyl, heteroaryl, or cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1177] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, and R6 is selected from:

[1178] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an 0-atom;

[1179] b) a 6 membered heteroaryl;

[1180] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[1181] d) phenyl; and

[1182] e) haloC1-6alkyl;

[1183] wherein the bicyclic edge-to-edge fused heterocycloalkyl, bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, cycloalkenyl, bridged cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1184] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, and R6 is selected from:

[1185] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an 0-atom;

[1186] b) a 6 membered heteroaryl;

[1187] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[1188] wherein the bicyclic edge-to-edge fused heterocycloalkyl; bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl, are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

[1189] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, and R6 is selected from:

[1190] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an 0-atom;

[1191] b) a 6 membered heteroaryl;

[1192] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[1193] wherein the bicyclic edge-to-edge fused heterocycloalkyl; bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl, are optionally substituted with one or two substituents independently selected from halogen, C1-6alkyl, and haloC1-6alkyl.

[1194] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, and R6 is selected from:

[1195] a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an 0-atom;

[1196] b) a 6 membered heteroaryl;

[1197] c) a 4-10 membered cycloalkyl selected from a saturated monocyclic 4-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;

[1198] wherein the bicyclic edge-to-edge fused heterocycloalkyl; bridged heterocycloalkyl, heteroaryl, saturated monocyclic cycloalkyl, or bicyclic edge-to-edge fused cycloalkyl, are optionally substituted with one or two substituents independently selected from Cl—, F—, CH3—, and CF3—.

[1199] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, and R6 is selected from dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH3CH2—, CF3—, cyclopropyl, CH3O—, cyano, and hydroxy.

[1200] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, and R6 is selected from dihydrochromenyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, and pyridinyl, wherein the dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyrimidinyl, or pyridinyl are optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH3CH2—, CF3—, cyclopropyl, CH3O—, cyano, and hydroxy.

[1201] In some embodiments, some compounds as described below, wherein R1 is C1-6alkoxy, are excluded from the compounds of formula (I).

[1202] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy selected from CH3O—, CH3CH2O—, CH3CH2CH2O—, and (CH3)3CO—.

[1203] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CH3O—.

[1204] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, and R2 and R3 are hydrogen.

[1205] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, R2 and R3 are hydrogen, and n is 0, 1, or 2.

[1206] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, R2 and R3 are hydrogen, n is 0, 1, or 2 and R6 is a 4-10 membered bridged cycloalkyl which is optionally substituted with one, two or three substituents independently selected from halogen, C1-6 alkyl, and haloC1-6alkyl.

[1207] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl which is optionally substituted with one, two or three substituents independently selected from halogen, C1-6 alkyl, and haloC1-6alkyl.

[1208] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl selected from bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, and bicyclo[2.2.2]octanyl, which are optionally substituted with one, two or three substituents independently selected from halogen, C1-6 alkyl, and haloC1-6alkyl.

[1209] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CH3O—, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl, which bridged cycloalkyl is unsubstituted.

[1210] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CH3O—, R2 and R3 are hydrogen, n is 0, and R6 is an unsubstituted bicyclo[2.2.1]heptanyl.

[1211] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CH3O—, R2 and R3 are hydrogen, n is 0, and R6 has the structure:

[1212] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CH3O—, R2 and R3 are hydrogen, n is 0, and R6 is a 4-10 membered bridged cycloalkyl, which bridged cycloalkyl is optionally substituted with one or two substituents independentyl selected from halogen, C1-6 alkyl, and haloC1-6alkyl.

[1213] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CH3O—, R2 and R3 are hydrogen, n is 0, and R6 is bicyclo[2.2.2]octanyl optionally substituted with one or two substituents independentyl selected from halogen, C1-6 alkyl, and haloC1-6alkyl.

[1214] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CH3O—, R2 and R3 are hydrogen, n is 0, and R6 is bicyclo[2.2.2]octanyl optionally substituted with one or two F— or CF3—.

[1215] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CH3O—, R2 and R3 are hydrogen, n is 0, and R6 has the structure:

[1216] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, R2 and R3 are hydrogen, n is 0, 1, or 2 and R6 is a saturated monocyclic 4-6 membered cycloalkyl which is optionally substituted with one, two or three substituents independently selected from halogen, C1-6 alkyl, and haloC1-6alkyl.

[1217] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl which is optionally substituted with one, two or three substituents independently selected from halogen, C1-6 alkyl, and haloC1-6alkyl.

[1218] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6alkoxy, R2 and R3 are hydrogen, n is 0, and R6 is a saturated monocyclic 4-6 membered cycloalkyl selected from cyclobutyl, cyclopentyl, and cyclohexyl, which are optionally substituted with one, two or three substituents independently selected from halogen, C1-6 alkyl, and haloC1-6alkyl.

[1219] In one embodiment, the present invention provides a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R1 is CH3O—, R2 and R3 are hydrogen, n is 0, and R6 is a saturated mon...

Claims

1. A pharmaceutical composition comprising a compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof:wherein:Y1 is CRa or N;Y2 is CRb or N;Y3 is CRc or N;provided that only 0 or 1 of Y1, Y2 and Y3 is N and the others are CRa, CRb, or CRc;Ra, Rb and Rc are each independently selected from hydrogen or halogen;R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, haloC1-6 alkylthio, C1-6alkoxy, a 4-6 membered heterocyclyloxy, 4-6 membered cycloalkyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl; wherein the heterocycloalkyl, heterocyclyloxy, and heteroaryl are optionally substituted with one C1-6alkyl, or haloC1-6alkyl; wherein the 4-6 membered cycloalkyloxy is optionally substituted with one, two, or three substituents independently selected from halogen; and wherein the haloC1-6alkoxy is optionally substituted with C1-6alkoxy;R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; orR2 and R3 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl and hydroxy; orR4 and R5 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy and Si(C1-6alkyl)3; wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, haloC1-6alkyl and C2-6 alkynyl; andn is 0, 1, 2, or 3.

2. A pharmaceutical composition according to claim 1 comprising a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, haloC1-6 alkylthio, C1-6alkoxy, a 4-6 membered heterocyclyloxy, 4-6 membered cycloalkyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl; wherein the heterocycloalkyl, heterocyclyloxy, and heteroaryl are optionally substituted with one C1-6alkyl, or haloC1-6alkyl; wherein the 4-6 membered cycloalkyloxy is optionally substituted with one, two, or three substituents independently selected from halogen; and wherein the haloC1-6alkoxy is optionally substituted with C1-6alkoxy;R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; orR2 and R3 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl and hydroxy; orR4 and R5 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy and Si(C1-6alkyl)3;wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, haloC1-6alkyl and C2-6 alkynyl; andn is 0, 1, 2, or 3.

3. A pharmaceutical composition comprising a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl; wherein the heterocycloalkyl, heterocyclyloxy, and heteroaryl are optionally substituted with one C1-6alkyl, or haloC1-6alkyl;R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; orR2 and R3 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, and hydroxy; orR4 and R5 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 4-10 membered cycloalkyl, phenyl, C1-6alkyl, and haloC1-6alkyl; wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; andn is 0, 1, 2, or 3.

4. A pharmaceutical composition according to any one of claims 1 to 3 comprising a compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:Y1, Y2 are CHY3 is selected from CH or N;R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, haloC1-6 alkylthio, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-5cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl; wherein the heterocycloalkyl, heterocyclyloxy, and heteroaryl are optionally substituted with one C1-6alkyl, or haloC1-6alkyl;R2 and R3 are independently selected from hydrogen, and hydroxyC1-6alkyl;R4 and R5 are independently selected from hydrogen, a saturated monocyclic 3-5 membered cycloalkyl, haloC1-6alkyl and C1-6alkyl, orR4 and R5 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, Si(C1-6alkyl)3 and phenyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, haloC1-6alkoxy, and haloC1-6alkyl; andn is 0, 1, or 2.

5. A pharmaceutical composition according to any one of claims 1 to 4 comprising a compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:Y1, Y2 are CHY3 is selected from CH or N;R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, haloC1-6 alkylthio, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-5cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, or 5 membered heteroaryl; wherein the heterocycloalkyl, heterocyclyloxy, and heteroaryl are optionally substituted with one C1-6alkyl, or haloC1-6alkyl;R2 and R3 are independently selected from hydrogen, and hydroxyC1-6alkyl;R4 and R5 are independently selected from hydrogen, a saturated monocyclic 3-5 membered cycloalkyl, haloC1-6alkyl and hydroxyC1-6alkyl,R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, Si(C1-6alkyl)3 and phenyl, wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, hydroxy, haloC1-6alkoxy and haloC1-6alkyl; andn is 0, 1, or 2.

6. A pharmaceutical composition according to any one of claims 1-5, wherein the compound of formula (I′) or (I) excludes compounds in which all of the following applies:R1 isR6 is:n is 2, and R4 and R5 are (i) all hydrogen or (ii) within the first pair of R4 and R5 both are hydrogen and within the second pair of R4 and R5 one is hydrogen and the other one is hydroxy.

7. A pharmaceutical composition according to any one of claims 1-6, wherein the compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

8. A pharmaceutical composition according to any one of claims 1-7, wherein the compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R6 is selected from a saturated monocyclic 3-6 membered cycloalkyl, a 7-10 membered bicycylic fused cycloalkyl, a 4-10 membered bridged cycloalkyl, a saturated monocyclic 3-6 membered cycloalkyl group, a 7-10 membered bicycylic fused cycloalkyl, phenyl, Si(C1-6alkyl)3 and a haloC1-6alkyl.

9. A pharmaceutical composition according to any one of claims 1-8, wherein the compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, wherein R6 is selected from a saturated monocyclic 3-6 membered cycloalkyl, a 7-10 membered bicycylic fused cycloalkyl, a 4-10 membered bridged cycloalkyl, a saturated monocyclic 3-6 membered cycloalkyl group, and a 7-10 membered bicycylic fused cycloalkyl.

10. A pharmaceutical composition according to any one of claims 1-9, wherein the pharmaceutical composition further comprises one or more pharmaceutical excipients.

11. A compound of formula (I′), or a solvate or a pharmaceutically acceptable salt thereof:wherein:Y1 is CRa or N;Y2 is CRb or N;Y3 is CRc or N;provided that only 0 or 1 of Y1, Y2 and Y3 is N and the others are CRa, CRb, or CRc;Ra, Rb and Rc are each independently selected from hydrogen or halogen;R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, haloC1-6 alkylthio, C1-6alkoxy, a 4-6 membered heterocyclyloxy, 4-6 membered cycloalkyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl; wherein the heterocycloalkyl, heterocyclyloxy, and heteroaryl are optionally substituted with one C1-6alkyl, or haloC1-6alkyl; wherein the 4-6 membered cycloalkyloxy is optionally substituted with one, two, or three substituents independently selected from halogen; and wherein the haloC1-6alkoxy is optionally substituted with C1-6alkoxy;R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; orR2 and R3 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl and hydroxy; orR4 and R5 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy and Si(C1-6alkyl)3; wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, haloC1-6alkyl and C2-6 alkynyl; andn is 0, 1, 2, or 3.

12. A compound according to claim 11 wherein the compound is of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, haloC1-6 alkylthio, C1-6alkoxy, a 4-6 membered heterocyclyloxy, 4-6 membered cycloalkyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl; wherein the heterocycloalkyl, heterocyclyloxy, and heteroaryl are optionally substituted with one C1-6alkyl, or haloC1-6alkyl; wherein the 4-6 membered cycloalkyloxy is optionally substituted with one, two, or three substituents independently selected from halogen; and wherein the haloC1-6alkoxy is optionally substituted with C1-6alkoxy;R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; orR2 and R3 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, haloC1-6alkyl and hydroxy; orR4 and R5 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, phenyl, C1-6alkyl, haloC1-6alkyl, haloC1-6alkoxy and Si(C1-6alkyl)3; wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, haloC1-6alkyl and C2-6 alkynyl; andn is 0, 1, 2, or 3.

13. A compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof:wherein:R1 is selected from a 4-6 membered heterocycloalkyl, cyano, haloC1-6alkoxy, C1-6alkoxy, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-8cycloalkylC1-6alkoxy, cyanoC1-6alkoxy, and 5 membered heteroaryl; wherein the heterocycloalkyl, heterocyclyloxy, and heteroaryl are optionally substituted with one C1-6alkyl, or haloC1-6alkyl;R2 and R3 are independently selected from hydrogen, deuterium, C1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, and hydroxyC1-6alkyl; orR2 and R3 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;R4 and R5 are independently selected from hydrogen, deuterium, C1-6alkyl, saturated monocyclic 3-5 membered cycloalkyl, C1-6alkoxy, hydroxyC1-6alkyl, and hydroxy; orR4 and R5 together with the one carbon atom to which they are attached form a saturated monocyclic 3-5 membered cycloalkyl;R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 4-10 membered cycloalkyl, phenyl, C1-6alkyl, and haloC1-6alkyl; wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl; andn is 0, 1, 2, or 3.

14. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11 to 13 wherein:Y1, Y2 are CH;Y3 is selected from CH or N.

15. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11 to 14, wherein R1 is selected from cyano, haloC1-6alkoxy, haloC1-6 alkylthio, a 4-6 membered heterocyclyloxy, halogen, haloC1-6alkyl, C3-5cycloalkylC1-6alkoxy, and cyanoC1-6alkoxy; wherein the heterocyclyloxy and cycloakylalkoxy are optionally substituted with one C1-6alkyl or haloC1-6alkyl.

16. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11 to 15, wherein R1 is selected from cyano, haloC1-6alkoxy, haloC1-6 alkylthio, and haloC1-6alkyl.

17. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11 to 15, wherein R1 is selected from cyano, CHF2O—, CHF2S—, CH3CF2O—, CH3CFHCH2O—, CF3CH2O—, CH3CF2—, CHF2—, and CF3—.

18. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 17, wherein R1 is selected from CHF2O—, CHF2S—, CH3CF2O—, CH3CFHCH2O—, and CF3CH2O—.

19. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 17 or 18, wherein R1 is CHF2O— or CH3CF2O—.

20. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11 to 14, wherein R1 is 5 membered heteroaryl selected from pyrazolyl and imidazolyl which are optionally substituted with one, two, or three substituents independently selected from halogen or haloC1-6alkyl.

21. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 20, wherein R1 is unsubstituted pyrazolyl or unsubstituted imidazolyl.

22. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof according to any one of claims 11 to 21, wherein (i) both R2 and R3 are hydrogen, or (ii) one of R2 and R3 is hydrogen and the other one is hydroxyC1-6alkyl.

23. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 22, wherein one of R2 and R3 is hydrogen and the other one is hydroxyC1-6alkyl selected from HOCH2—, HOCH2CH2—, HOCH2CH2CH2—, and HOCH2CH2CH2CH2—.

24. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 23, wherein the hydroxyC1-6alkyl is HOCH2— or HOCH2CH2—.

25. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 22, wherein both R2 and R3 are hydrogen.

26. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11 to 25, wherein n is 0 or 1.

27. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 26, wherein n is 0.

28. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 26, wherein n is 1.

29. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 28, wherein n is 1 and (i) both R4 and R5 are hydrogen, (ii) one of R4 and R5 is hydrogen and the other one is C1-6alkyl, haloC1-6alkyl, a saturated monocyclic 3-5 membered cycloalkyl, or C1-6alkoxy.

30. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 29, wherein one of R4 and R5 is hydrogen and the other one is a methyl (CH3—) or methoxy (CH3O—).

31. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 29, wherein one of R4 and R5 is hydrogen and the other one is a trifluoromethyl (—CF3) or difluoromethyl (—CHF2).

32. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 29, wherein the saturated monocyclic 3-5 membered cycloalkyl is unsubstituted cyclopropyl.

33. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 29, wherein n is 1 and both R4 and R5 are hydrogen.

34. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11-29, wherein R4 and R5, together with the one carbon atom to which they are attached, form cyclopropyl.

35. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof according to any one of claims 11-34, wherein R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, a 3-10 membered cycloalkyl, C1-6alkyl, haloC1-6alkyl, Si(C1-6alkyl)3 and phenyl; wherein the heterocycloalkyl, heteroaryl, cycloalkyl, or phenyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

36. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof according to any one of claims 11-35, wherein R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, and a 3-10 membered cycloalkyl; wherein the heterocycloalkyl, heteroaryl, or cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C3-6cycloalkyl, C1-6alkoxy, haloC1-6alkoxy, cyano, oxo, hydroxy, hydroxyC1-6alkyl, and haloC1-6alkyl.

37. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 36, wherein R6 is optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CH2F—, CF3—, (CH3)2CF—, cyclopropyl, and CH3O—, CF30—, CHF2O—, cyano, and hydroxy.

38. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 37, wherein R6 is optionally substituted with one, two, or three substituents independently selected from Cl—, F—, CH3—, CF3—, cyclopropyl, CH3O—, CF30— and CHF2O—.

39. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 37 or 38, wherein R6 is optionally substituted with one, two, or three substituents independently selected from F—, CF3—, CF30— and CHF2O—.

40. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 35-39, wherein R6 is selected from:a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an 0-atom;b) a 6 membered heteroaryl;c) a 3-10 membered cycloalkyl selected from a saturated monocyclic 3-6 membered cycloalkyl, a 6 membered cycloalkenyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings;d) phenyl;e) C1-6alkyl;f) haloC1-6alkyl;g) Si(C1-6alkyl)3; andoptionally substituted according to any one of claims 35-39.

41. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 40, wherein R6 is selected from:a) a 5-12 membered heterocycloalkyl, which heterocycloalkyl is selected from a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom; a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom; and a 7-10 membered bridged heterocycloalkyl, wherein the bridge comprises an 0-atom;b) a 6 membered heteroaryl; andc) a 3-10 membered cycloalkyl selected from a saturated monocyclic 3-6 membered cycloalkyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings.

42. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 35-41, wherein R6 is selected from:dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, tert-butyl, bicyclo[2.2.2]octanyl, (CH3)2CF—, CHF2—, Si(CH3)3, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyridinyl, and pyrimidinyl.

43. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 35-42, wherein R6 is selected from:dihydrochromenyl, cyclopentyl, phenyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclohexenyl, cyclobutyl, bicyclo[2.2.2]octanyl, bicyclo[3.1.0]hexanyl, oxolanyl, octahydropentalenyl, hexahydrocyclopenta[b]furanyl, pyrazinyl, pyridinyl, and pyrimidinyl.

44. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 35-43, wherein R6 is selected from:

45. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 44, wherein R6 is selected from:

46. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 35-45, wherein R1 is selected from CHF2O—, unsubstituted pyrazolyl, unsubstituted imidazolyl, CH3O—, (CH3)CF2—, CN—, CHF2—, CF3—, CF3CH2O—, CH3CFHCH2O—, CF2H—S—, R2 and R3 are hydrogen, n is 0 or 1, (i) R4 and R5 are hydrogen, or (ii) one of R4 and R5 is hydrogen and the other is cyclopropyl, or (iii) one of R4 and R5 is hydrogen and the other is selected from CF3—, CHF2, and CH2F or (iv) R4 and R5 together with the one carbon atom to which they are attached, form cyclopropyl, and R6 is selected from a 5-12 membered heterocycloalkyl which heterocycloalkyl is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom, a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom, a 7-10 membered bridged heterosystem, wherein the bridge comprises an O-atom, a 6 membered heteroaryl; and a 3-10 membered cycloalkyl selected from cyclopropyl, a saturated monocyclic 4-6 membered cycloalkyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings, all optionally substituted according to any one of claims 35-39 and 44-45.

47. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 46, wherein R1 is selected from CF3CH2O—, CHF2O— or unsubstituted imidazolyl, R2 and R3 are hydrogen, n is 0 or 1, (i) R4 and R5 are hydrogen, or (ii) one of R4 and R5 are hydrogen and the other is cyclopropyl, or (iii) one of R4 and R5 is hydrogen and the other is selected from CF3—, CHF2, and CH2F, or (iii) R4 and R5 together with the one carbon atom to which they are attached, form cyclopropyl, and R6 is selected from a 5-12 membered heterocycloalkyl which heterocycloalkyl is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom, a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one 0-atom or one N-atom, a 7-10 membered bridged heterosystem, wherein the bridge comprises an O-atom; a 6 membered heteroaryl; and a 3-10 membered cycloalkyl selected from cyclopropyl, a saturated monocyclic 4-6 membered cycloalkyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings, all optionally substituted according to any one of claims 34-38 and 43-44.

48. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 46 or 47, wherein R1 is selected from CF3CH2O—, CHF2O— and unsubstituted imidazolyl, R2 and R3 are hydrogen, n is 0; and R6 is selected from a 5-12 membered heterocycloalkyl which heterocycloalkyl is a bicyclic edge-to-edge fused heterocycloalkyl comprising one aliphatic and one aromatic ring, wherein one ring comprises one O-atom, a 7-10 membered bicyclic edge-to-edge fused heterocycloalkyl comprising two aliphatic rings, wherein the one ring comprises one O-atom or one N-atom, a 7-10 membered bridged heterosystem, wherein the bridge comprises an O-atom; a 6 membered heteroaryl; and a 3-10 membered cycloalkyl selected from cyclopropyl, a saturated monocyclic 4-6 membered cycloalkyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings; all optionally substituted according to any one of claims 34-38 and 43-44.

49. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 46-48, wherein R1 is CF3CH2O—, or CHF2O— and R6 is substituted with one or two F— or CF3—, or R6 is CF3—.

50. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 49, wherein R1 is CHF2O— and R6 is selected from a saturated monocyclic 4-6 membered cycloalkyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings; all substituted with one or two F— or CF3—.

51. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 35-49 wherein R1 is CHF2O—, n is 0 or 1, and R6 is selected from a 5-12 membered heterocycloalkyl, a 6 membered heteroaryl, and a 4-10 membered cycloalkyl; all substituted with substituted with one or two F— or CF3—.

52. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to 51, wherein R6 is selected from a saturated monocyclic 4-6 membered cycloalkyl, a 4-10 membered bridged cycloalkyl, and a 7-10 membered bicyclic edge-to-edge fused cycloalkyl comprising two aliphatic rings; all substituted with one or two F— or CF3—.

53. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11-52, or a pharmaceutical composition according to any one of claims 1-9, wherein the compound is selected from:ExampleNameStructure11-[(4R)-3,4- dihydro-2H- chromen-4-yl]-3- [(2-pyrazol-1- ylpyridin-4- yl)methyl]urea21-cyclopentyl-3- [(2-pyrazol-1- ylpyridin-4- yl)methyl]urea41-(3- chlorophenyl)-3- [(2-pyrazol-1- ylpyridin-4- yl)methyl]urea51-[(2- cyanopyridin-4- yl)methyl]-3- (2,4,4- trimethylcyclo- hexyl)urea61-[(2-pyrazol-1- ylpyridin-4- yl)methyl]-3-[3- (trifluoromethyl)- 1- bicyclo[1.1.1] pentanyl]urea71-[(2-pyrazol-1- ylpyridin-4- yl)methyl]-3-[rac- (1R,2R,4S)-2- bicyclo[2.2.1] heptanyl]urea81-(3- cyclopropylcyclo- hexyl)-3-[(2- imidazol-1- ylpyridin-4- yl)methyl]urea91-[(2-imidazol-1- ylpyridin-4- yl)methyl]-3- (2,4,4- trimethylcyclo- hexyl)urea101-[2-(cyclohexen- 1-yl)ethyl]-3-[(2- pyrazol-1- ylpyridin-4- yl)methyl]urea121-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,2R,4S)-2- bicyclo[2.2.1] heptanyl]urea131- (cyclobutylmethyl)- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea141-[(2- methoxypyridin-4- yl)methyl]-3-[rac- (1R,2R,4S)-2- bicyclo[2.2.1] heptanyl]urea151-[(1S,2S,4R)-2- bicyclo[2.2.1] heptanyl]-3-[(2- pyrazol-1- ylpyridin-4- yl)methyl]urea161-[(1R,2R,4S)-2- bicyclo[2.2.1] heptanyl]-3-[(2- pyrazol-1- ylpyridin-4- yl)methyl]urea171-(1- cyclobutylethyl)- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea181-(4,4- dimethylcyclo- hexyl)-3-[[2-(oxetan- 3-yloxy)pyridin-4- yl]methyl]urea201-cyclopentyl-3- [[2- (difluoromethoxy) pyridin-4- yl]methyl]urea211- (cyclobutylmethyl)- 3-[[2-(2,2,2- trifluoroethoxy) pyridin-4- yl]methyl]urea221-(3- chlorophenyl)-3- [[2- (difluoromethoxy) pyridin-4- yl]methyl]urea231-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- [(4R)-3,4-dihydro- 2H-chromen-4- yl]urea241-[1-(2- bicyclo[2.2.1] heptanyl)ethyl]- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea251-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(2,6- dimethylcyclo- hexyl)urea261-[rac- (1R,2R,4S)-2- bicyclo[2.2.1] heptanyl]-3-[[2-[4- (trifluoromethyl) imidazol-1- yl]pyridin-4- yl]methyl]urea271-[(2- bromopyridin-4- yl)methyl]-3-[rac- (1R,2R,4S)-2- bicyclo[2.2.1] heptanyl]urea281-[[2-(1,3-oxazol- 5-yl)pyridin-4- yl]methyl]-3-[rac- (1R,2R,4S)-2- bicyclo[2.2.1] heptanyl]urea291-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(2,2- dimethylpropyl)urea311-(1- bicyclo[1.1.1] pentanylmethyl)- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea321-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[(3- fluoro-1- bicyclo[1.1.1] pentanyl)methyl] urea331-[[2-(1,1- difluoroethyl) pyridin-4-yl] methyl]- 3-[rac-(1R,2R,4S)- 2- bicyclo[2.2.1] heptanyl]urea341-[(2- cyanopyridin-4- yl)methyl]-3-[rac- (1R,2R,4S)-2- bicyclo[2.2.1] heptanyl]urea351-[[2- (difluoromethyl) pyridin-4- yl]methyl]-3-[rac- (1R,2R,4S)-2- bicyclo[2.2.1] heptanyl]urea361-[rac- (1R,2R,4S)-2- bicyclo[2.2.1] heptanyl]-3-[[2- (trifluoromethyl) pyridin-4- yl]methyl]urea371-(4,4- dimethylcyclo- hexyl)-3-[(2- imidazol- 1-ylpyridin-4- yl)methyl]urea381-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[(1- methoxycyclobutyl) methyl]urea391-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(2- fluoro-2- methylpropyl)urea401-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[(1- fluorocyclobutyl) methyl]urea411- (cyclobutylmethyl)- 3-[[2-[4- (trifluoromethyl) imidazol-1- yl]pyridin-4- yl]methyl]urea421-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- [(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea431-cyclopentyl-3- [[2-(2,2,2- trifluoroethoxy) pyridin-4- yl]methyl]urea441-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[1- (2,2- dimethylpropyl) cyclopropyl]urea451-cyclobutyl-3- [[2- (difluoromethoxy) pyridin-4- yl]methyl]urea461- (cyclopentylmethyl)- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea471-(1- bicyclo[1.1.1] pentanyl)-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea481-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(4- fluoro-1- bicyclo[2.2.2] octanyl)urea491-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(3- methoxy-1- bicyclo[1.1.1] pentanyl)urea501-(1- cyclobutylcyclo- propyl)-3-[2- (difluoromethoxy) pyridin-4- yl]methyl]urea541-[[2- (cyclobutylmethoxy) pyridin-4- yl]methyl]-3- [(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea551-[[2- (cyclopropyl- methoxy)pyridin-4- yl]methyl]-3- [(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea561-[[2-(2,2- difluoroethoxy) pyridin-4-yl]methyl]- 3-[(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea571-[[2-(1,1- difluoroethyl)pyri- din-4-yl]methyl]- 3-[(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea581-[(1r,3r)-3- (trifluoromethyl) cyclobutyl]-3-[2- (trifluoromethyl) pyridin-4- yl]methyl]urea591-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,3S)-3- (trifluoromethyl) cyclopentyl]urea601-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(3- ethylcyclobutyl)urea621-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[[3- (trifluoromethyl) cyclobutyl]methyl] urea631-[[2- (cyanomethoxy) pyridin-4-yl]methyl]- 3-[(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea641-[[2-(2,2,2- trifluoroethyl) pyridin-4-yl]methyl]- 3-[(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea651-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(3- methylcyclobutyl) urea661-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(3- ethynylcyclobutyl) urea671-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- ((1r,3r)-3- fluorocyclobutyl) urea681-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[4- (trifluoromethyl)- 1- bicyclo[2.2.2] octanyl]urea711-[[2-(2,2,2- trifluoroethoxy) pyridin-4-yl]methyl]- 3-[[3- (trifluoromethyl) cyclobutyl]methyl] urea731-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,5R)-6,6- difluoro-2- bicyclo[3.1.0] hexanyl]urea741-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,5S)-6,6- difluoro-3- bicyclo[3.1.0] hexanyl]urea751-[(3-fluoro-1- bicyclo[1.1.1] pentanyl)methyl]-3- [[2-(2,2,2- trifluoroethoxy) pyridin-4- yl]methyl]urea761-[(1R,3aR,6aR)- 1,2,3,3a,4,5,6,6a- octahydropentalen- 1-yl]-3-[2- (difluoromethoxy) pyridin-4- yl]methyl]urea771-(3- cyclopropylcyclo- butyl)-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea781- (1,2,3,3a,4,5,6,6a- octahydropentalen- 2-yl)-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea791-[rac-(1R,3S)-3- (trifluoromethyl) cyclopentyl]-3-[[2- (2,2,2- trifluoroethoxy) pyridin-4- yl]methyl]urea811-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,2S)-2- hydroxy-3,3- dimethylcyclobutyl] urea821-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(4- fluoro-2-hydroxy- 1- bicyclo[2.2.2] octanyl)urea831-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(3- methoxyphenyl) urea841-(6- chloropyridin-2- yl)-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea851-[1-[2- (difluoromethoxy) pyridin-4-yl]-2- hydroxyethyl]-3- (4-fluoro-1- bicyclo[2.2.2] octanyl)urea871-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[[3- (1r,3r)- (trifluoromethyl) cyclobutyl]methyl] urea881-(4-fluoro-1- bicyclo[2.2.2] octanyl)-3-[[2-(2- fluoropropoxy) pyridin-4- yl]methyl]urea891-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[(3- fluorocyclobutyl) methyl]urea901-(4,4- difluorocyclohexyl)- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea911-[1-[2- (difluoromethoxy) pyridin-4-yl]-2- hydroxyethyl]-3- [(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea921-(3- chlorophenyl)-3- [2-hydroxy-1-[2- (2,2,2- trifluoroethoxy) pyridin-4- yl]ethyl]urea931-(3,3- difluorocyclopentyl)- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea951-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(2- hydroxy-3,3- dimethylbutyl)urea961-(4- chloropyrimidin- 2-yl)-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea971-(3- chlorophenyl)-3- [1-[2- (difluoromethoxy) pyridin-4-yl]-2- hydroxyethyl]urea981-(6- chloropyrazin-2- yl)-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea991-[rac-(1R,2S)-2- hydroxy-3,3- dimethylcyclobutyl]- 3-[[2-[4- (trifluoromethyl) imidazol-1- yl]pyridin-4- yl]methyl]urea1001-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- [(1s,3s)-3- hydroxy-3- (trifluoromethyl) cyclobutyl]urea1011-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,2R)-2- hydroxy-5,5- dimethylcyclohexyl] urea1021-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,2S,4S)-7- oxabicyclo[2.2.1] heptan-2-yl]urea1031-[(1S,3aS,6aS)- 1,2,3,3a,4,5,6,6a- octahydropentalen- 1-yl]-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1051-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- [(3aR,6aS)- 1,2,3,3a,4,5,6,6a- octahydropentalen- 2-yl]urea1061-(1-cyclopropyl- 2,2,2- trifluoroethyl)-3- [[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1071-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,2S,4S,6R)-6- hydroxy-2- bicyclo[2.2.1] heptanyl]urea1081-(3,3- difluorocyclobutyl)- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1091-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(3,3- dimethylbutyl)urea1101-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[1- (2,2,2- trifluoroethyl) cyclopropyl]urea1111-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,5S,6S,7R)-7- hydroxy-6- bicyclo[3.2.0] heptanyl]urea1121-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (2R,3aS,6aS)-6a- (hydroxymethyl)- 2,3,3a,4,5,6- hexahydro-1H- pentalen-2-yl]urea1131-(2,2- difluorocyclopentyl)- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1141-(3,3a,4,5,6,6a- hexahydro-1H- cyclopenta[c]pyrrol- 2-yl)-3-[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1151-[(1R)-3,3- difluorocyclopentyl]- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1161-[(1S)-3,3- difluorocyclopentyl]- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1171-[1-[2- (difluoromethoxy) pyridin-4-yl]-3- hydroxypropyl]-3- [(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea1181-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,2S)-2- hydroxycyclo- pentyl]urea1191-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- (3,3,3-trifluoro-2- methoxypropyl)urea1201-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[[rac- (3aR,6aR)- 2,3,3a,4,5,6- hexahydrocyclo- penta[b]furan-6a- yl]methyl]urea1211-[[2-(2,2- difluoropropoxy) pyridin-4- yl]methyl]-3- [(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea1221-[[2-(2,2- difluoropropoxy) pyridin-4- yl]methyl]-3-(4- fluoro-1- bicyclo[2.2.2] octanyl)urea1231-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,2S)-2- fluorocyclobutyl] urea1251- [cyclobutyl (dideuterio)methyl]- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1261-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(3- methylphenyl)urea1281-[(2- methoxypyridin-4- yl)methyl]-3- [(1r,3r)-3- (trifluoromethyl) cyclobutyl]urea1291-(4-fluoro-1- bicyclo[2.2.2] octanyl)-3-[(2- methoxypyridin-4- yl)methyl]urea1311-(1- bicyclo[2.2.2] octanyl)-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1321-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[3- (fluoromethyl) phenyl]urea1331-[(1R,2R,5R)- 6,6-difluoro-2- bicyclo[3.1.0] hexanyl]-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1341-[(1R)-1- cyclopropyl-2,2,2- trifluoroethyl]-3- [2- (difluoromethoxy) pyridin-4- yl]methyl]urea1351-[(1S)-1- cyclopropyl-2,2,2- trifluoroethyl]-3- [[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1361-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[3- (difluoromethyl) cyclobutyl]urea1371-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- [(1s,3s)-3- (difluoromethyl) cyclobutyl]urea1381-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,3S)-3- (trifluoromethyl) cyclohexyl]urea1391-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,5S)-3-oxo-8- bicyclo[3.2.1] octanyl]urea1401-[(1S)-3,3- difluorocyclohexyl]- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1421-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(3,3- difluoro-1- methylcyclopentyl) urea1431-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-(4,4- difluoro-1- methylcyclohexyl) urea1441-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- [(1S,3R)-3- (trifluoromethyl) cyclopentyl]urea1451-(3- chlorophenyl)-3- [(1R)-2-hydroxy- 1-[2-(2,2,2- trifluoroethoxy) pyridin-4- yl]ethyl]urea1461-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- [(1R,3S)-3- (trifluoromethyl) cyclopentyl]urea1471-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[2- hydroxy-2- (trifluoromethyl) cyclohexyl]urea1481-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,2R)-2- hydroxy-2- methylcyclohexyl] urea1491-[(1R)-3,3- difluorocyclohexyl]- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1501-(3-chloro-2- fluorophenyl)-3- [2-hydroxy-1-[2- (2,2,2- trifluoroethoxy) pyridin-4- yl]ethyl]urea1511-(4-fluoro-1- bicyclo[2.2.2] octanyl)- 3-[[2-[(2R)-2- fluoropropoxy] pyridin-4- yl]methyl]urea1521-(1-cyclobutyl- 2,2,2- trifluoroethyl)-3- [[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1531-(3-fluoro-1- bicyclo[1.1.1] pentanyl)-3-[[2- (trifluoromethyl) pyridin-4- yl]methyl]urea1541-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,2R)-4,4- difluoro-2- hydroxycyclohexyl] urea1561-(4-fluoro-1- bicyclo[2.2.2] octanyl)- 3-[[2-[(2S)-2- fluoropropoxy] pyridin-4- yl]methyl]urea1571-(3,3- difluorocyclobutyl)- 3-[[2-(2,2,2- trifluoroethoxy) pyridin-4- yl]methyl]urea1591-(3-fluoro-1- bicyclo[1.1.1] pentanyl)- 3-[[2-(2,2,2- trifluoroethyl) pyridin-4- yl]methyl]urea1601-(3-fluoro-1- bicyclo[1.1.1] pentanyl)-3-[[2-(2- fluoropropoxy) pyridin-4- yl]methyl]urea1611-(5- chloropyridin-3- yl)-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1621-((1r,3r)-3- fluorocyclobutyl)- 3-[[2-(2,2,2- trifluoroethoxy) pyridin-4- yl]methyl]urea1631-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3- ((1r,3r)-3- methylcyclobutyl) urea1641-(3- chlorophenyl)-3- [2- (fluoromethoxy) pyridin-4- yl]methyl]urea1651-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,4R)-5,5- difluoro-2- bicyclo[2.2.1] heptanyl]urea1661-(5- cyclopropyloxolan- 3-yl)-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1681-(3-fluoro-1- bicyclo[1.1.1] pentanyl)- 3-[[2-(2,2,2- trifluoroethoxy) pyridin-4- yl]methyl]urea1691-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,5S)-6,6- difluoro-3- bicyclo[3.1.0] hexanyl]urea1701-[(1R,5S,6R)- 2,2-difluoro-6- bicyclo[3.1.0] hexanyl]-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1711-[1-(3,3- difluorocyclobutyl) cyclopropyl]-3- [[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1721-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[rac- (1R,5S,6R)-2,2- difluoro-6- bicyclo[3.1.0] hexanyl]urea1731-(2,2- difluorocyclopropyl)- 3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1741-[(1S,5R,6S)-2,2- difluoro-6- bicyclo[3.1.0] hexanyl]-3-[[2- (difluoromethoxy) pyridin-4- yl]methyl]urea1751-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[1- (trifluoromethyl) cyclopropyl]urea1761-[[2- (fluoromethoxy) pyridin-4-yl]methyl]- 3-[rac-(1R,5S,6R)- 2,2-difluoro-6- bicyclo[3.1.0] hexanyl]urea1771-[[2- (difluoromethoxy) pyridin-4- yl]methyl]-3-[1- (3-fluoro-1- bicyclo[1.1.1] pentanyl) cyclopropyl]urea54. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11-52, or a pharmaceutical composition according to any one of claims 1-9, wherein the compound is selected from:ExampleNameStructure1781-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[3-(trifluoromethyl)- 1-bicyclo[1.1.1]pentanyl]urea 1791-[[2-(2,2,2-trifluoroethoxy)pyridin- 4-yl]methyl]-3-[(1r,3r)-3-(trifluoromethyl) cyclobutyl]urea1801-(4-fluoro-1-bicyclo[2.2.2]octanyl)-3-[[2- (2,2,2-trifluoroethoxy)pyridin-4-yl] methyl]urea 1811-[(3,3-difluorocyclobutyl)methyl]-3-[[2- (difluoromethoxy)pyridin-4-yl]methyl]urea 1821-[[2-(difluoromethoxy)pyridin-4-yl]methyl]- 3-(3-methyl-1-bicyclo[1.1.1]pentanyl)urea 1831-[[2-(2-fluoropropoxy)pyridin-4-yl]methyl]- 3-[(1r,3r)-3-(trifluoromethyl)cyclobutyl]urea 1841-[[2-(difluoromethoxy)pyridin-4-yl]methyl]- 3-[(1S,2S)-2-hydroxy-2-methylcyclopentyl]urea1851-[2-hydroxy-1-[2-(2,2,2-trifluoro- ethoxy)pyridin-4-yl]ethyl]-3-[(1r,3r)-3- (trifluoromethyl)cyclobutyl]urea1861-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-(3,4-difluorophenyl)urea1871-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[rac-(1R,3S)-3-hydroxy- 3-(trifluoromethyl)cyclopentyl]urea1881-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-(3,3-dimethylcyclobutyl)urea1891-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[(1R,3r,5S)-6,6-difluoro-3- bicyclo[3.1.0]hexanyl]urea 1901-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[(2s,3aR,6aS)- 1,2,3,3a,4,5,6,6a-octahydropentalen-2-yl]urea1911-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[[1-(difluoromethyl)cyclobutyl] methyl]urea1921-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-(3,4-dihydro-2H-chromen-3-yl)urea1931-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[rac-(1R,3S)-3- (difluoromethyl)cyclopentyl]urea1941-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[(1r,3r)-1-methyl-3- (trifluoromethyl)cyclobutyl]urea1951-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[(2r,3aR,6aS)-5,5- difluoro-2,3,3a,4,6,6a-hexahydro- 1H-pentalen-2-yl]urea1961-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[rac-(1R,5R)-2- bicyclo[3.2.0]heptanyl]urea1971-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[rac-(1R,5S)-3,3-difluoro- 8-bicyclo[3.2.1]octanyl]urea1981-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[(1s,3s)-3- (trifluoromethyl)cyclobutyl]urea1991-[[2-[(2R)-2-fluoropropoxy]pyridin-4- yl]methyl]-3-[(1r,3r)-3-(trifluoromethyl) cyclobutyl]urea2001-[[2-(1,1-difluoroethyl)pyridin-4- yl]methyl]-3-(3-fluoro-1- bicyclo[1.1.1 ]pentanyl)urea2011-[[2-(2,2-difluoropropoxy)pyridin-4- yl]methyl]-3-(3-fluoro-1- bicyclo[1.1.1]pentanyl)urea2021-[[2-[(2S)-2-fluoropropoxy]pyridin-4- yl]methyl]-3-[(1r,3r)-3-(trifluoro- methyl)cyclobutyl]urea2031-(3-chlorophenyl)-3-[[2-(2,2,2- trifluoroethoxy)pyrimidin-4-yl]methyl]urea2041-[[2-(2,2,2-trifluoroethoxy)pyrimidin-4- yl]methyl]-3-[(1r,3r)-3- (trifluoromethyl)cyclobutyl]urea2051-(4-fluoro-3-methylphenyl)-3- [2-hydroxy-1-[2-(2,2,2-trifluoro- ethoxy)pyridin-4-yl]ethyl]urea2061-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[(1R,3R)-3-(trifluoro- methyl)cyclopentyl]urea2071-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[(1S,3S)-3-(trifluoro- methyl)cyclopentyl]urea2081-(4-fluoro-1-bicyclo[2.2.2]octanyl)-3-[[2- (fluoromethoxy)pyridin-4-yl]methyl]urea2091-[[2-(3,3-difluorocyclobutyl)oxypyridin-4- yl]methyl]-3-[(1r,3r)-3-(trifluoro- methyl)cyclobutyl]urea2101-[(1-fluorocyclobutyl)methyl]-3-[[2-(2,2,2- trifluoroethoxy)pyridin-4-yl]methyl]urea2111-[[2-(difluoromethoxy)pyridin-4-yl]methyl]-3- [(1s,4s)-4-(trifluoromethyl)cyclohexyl]urea2121-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-(2-trimethylsilylethyl)urea2131-[[2-(2,3-difluoropropoxy)pyridin-4-yl]methyl]- 3-(4-fluoro-1-bicyclo[2.2.2]octanyl)urea2141-[[2-(2,3-difluoropropoxy)pyridin-4- yl]methyl]-3-[(1r,3r)-3-(trifluoro- methyl)cyclobutyl]urea2151-[[6-(2,2,2-trifluoroethoxy)pyridazin-4- yl]methyl]-3-[(1r,3r)-3-(trifluoro- methyl)cyclobutyl]urea2161-[[2-(2,3-difluoropropoxy)pyridin-4- yl]methyl]-3-(3-fluoro-1-bicyclo[1.1.1] pentanyl)urea2171-[[2-(2,2-difluoroethoxy)pyridin-4- yl]methyl]-3-(3-fluoro-1-bicyclo[1.1.1] pentanyl)urea2181-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-(6-methylpyridin-2-yl)urea2191-[[2-(difluoromethoxy)-3-fluoropyridin-4- yl]methyl]-3-[(1r,3r)-3-(trifluoromethyl) cyclobutyl]urea2201-(3-chlorophenyl)-3-[[2-(2,3-difluoro- propoxy)pyridin-4-yl]methyl]urea 2211-[(1r,3r)-3-(trifluoromethyl)cyclobutyl]- 3-[2-(1,1,1-trifluoropropan-2-yloxy)pyridin-4- yl]methyl]urea2221-(7,7-difluoro-3-bicyclo[4.1.0]heptanyl)-3-[[2- (difluoromethoxy)pyridin-4-yl]methyl]urea2231-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-3-[[2- (1,1,1-trifluoropropan-2-yloxy)pyridin-4- yl]methyl]urea2241-[[2-(3,3-difluorocyclobutyl)oxypyridin-4- yl]methyl]-3-(3-fluoro-1-bicyclo[1.1.1] pentanyl)urea2251-[[2-(2,3-difluoropropoxy)pyridin-4- yl]methyl]-3-[rac-(1R,3S)-3- (trifluoromethyl)cyclopentyl]urea2261-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[2-(trifluoromethyl)oxan-4-yl]urea2271-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[(1-fluorocyclopentyl)methyl]urea2281-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-(1,1,1,3,3,3-hexafluoropropan- 2-yl)urea2291-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[[1-(trifluoromethyl)cyclo- propyl]methyl]urea2301-[(1R)-1-(3,3-difluorocyclobutyl)-2,2- difluoroethyl]-3-[[2-(difluoromethoxy) pyridin-4-yl]methyl]urea2311-(3-chlorophenyl)-3-[[2-(1,1-difluoroethyl) pyridin-4-yl]methyl]urea2321-[3-(fluoromethyl)phenyl]-3-[2-hydroxy- 1-[2-(2,2,2-trifluoroethoxy)pyridin-4- yl]ethyl]urea2331-[2-hydroxy-1-[2-(2,2,2- trifluoroethoxy)pyridin-4-yl]ethyl]- 3-(3-methylphenyl)urea2341-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[rac-(3R,4S)-3,4- difluorocyclopentyl]urea2351-(3-cyclopropylcyclobutyl)-3-[[2-(2,2,2- trifluoroethoxy)pyridin-4-yl]methyl]urea2361-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[rac-(1R,2S,4S)-6,6- difluoro-2-bicyclo[2.2.1]heptanyl]urea2371-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-[[1-(trifluoromethyl)cyclo- butyl]methyl]urea2381-[(1R,3s,5S)-6,6-difluoro-3-bicyclo[3.1.0] hexanyl]-3-[[2-(2,2,2-trifluoroethoxy) pyridin-4-yl]methyl]urea2391-[[2-(difluoromethoxy)pyridin-4-yl]methyl]- 3-[(1S,3S)-3-fluorocyclopentyl]urea2401-[1-[2-(difluoromethoxy)pyridin-4-yl]-2- hydroxyethyl]-3-(3,4-difluorophenyl)urea2411-[(1R)-1-cyclobutyl-2,2,2-trifluoroethyl]-3-[2- (difluoromethoxy)pyridin-4-yl]methyl]urea2421-[(1S)-1-cyclobutyl-2,2,2-trifluoroethyl]-3- [[2-(difluoromethoxy)pyridin-4-yl]methyl]urea2431-[[2-(difluoromethoxy)pyrimidin-4- yl]methyl]-3-[(1r,3r)-3-(trifluoro- methyl)cyclobutyl]urea2441-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-(2,5-difluorophenyl)urea2451-(2,5-difluorophenyl)-3-[[2-(2,2,2- trifluoroethoxy)pyridin-4-yl]methyl]urea2461-[1-(1-bicyclo[1.1.1]pentanyl)cyclopropyl]-3-[[2- (difluoromethoxy)pyridin-4-yl]methyl]urea2471-[[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-(2,3-difluorophenyl)urea2481-(2,3-difluorophenyl)-3-[[2-(2,2,2- trifluoroethoxy)pyridin-4-yl]methyl]urea2491-(3,4-difluorophenyl)-3-[[2-(fluoromethoxy) pyridin-4-yl]methyl]urea2501-[[2-(difluoromethoxy)pyridin-4-yl]methyl]-3- [(1R,3S)-3-(trifluoromethyl)cyclohexyl]urea2511-[dideuterio-[2-(difluoromethoxy)pyridin-4- yl]methyl]-3-(4-fluoro-1-bicyclo[2.2.2]octanyl)urea2521-[[2-(difluoromethoxy)pyridin-4-yl]methyl]-3- [3,3,3-trifluoro-2-(trifluoromethyl)propyl]urea2531-(dicyclopropylmethyl)-3-[[2- (difluoromethoxy)pyridin-4-yl]methyl]urea2541-[1-(3,3-difluorocyclobutyl)cyclopropyl]-3- [[2-(2,2,2-trifluoroethoxy)pyridin-4-yl]methyl]urea2551-[[2-(difluoromethoxy)pyridin-4-yl]methyl]-3- [rac-(1R,2S)-2-(trifluoromethyl)cyclobutyl]urea2561-(3,5-difluorophenyl)-3-[2-hydroxy-1-[2- (2,2,2-trifluoroethoxy)pyridin-4-yl]ethyl]urea2571-[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]-3- [[2-(2,2,2-trifluoroethoxy)pyridin-4-yl]methyl]urea2581-[[2-(difluoromethoxy)pyridin-4-yl]methyl]- 3-[5-(trifluoromethyl)oxolan-3-yl]urea2591-(3-chlorophenyl)-3-[1-[2-(2,2-difluoro- ethoxy)pyridin-4-yl]-2-hydroxyethyl]urea2601-[[2-(difluoromethylsulfanyl)pyridin-4- yl]methyl]-3-[(1r,3r)-3-(trifluoromethyl) cyclobutyl]urea2611-[[2-(difluoromethoxy)pyridin-4-yl]methyl]-3- (4-fluoro-3-methylphenyl)urea2621-[3-(difluoromethoxy)phenyl]-3-[[2- (difluoromethoxy)pyridin-4-yl]methyl]urea263rel-1-(3-chlorophenyl)-3-[(1R)-1-[2-(difluoro- methoxy)pyridin-4-yl]-2-hydroxyethyl]urea2641-[3-(difluoromethoxy)cyclopentyl]-3-[[2- (difluoromethoxy)pyridin-4-yl]methyl]urea2651-[(1s,3s)-3-(difluoromethoxy)cyclobutyl]-3-[[2- (difluoromethoxy)pyridin-4-yl]methyl]urea2661-[(1r,4r)-4-(difluoromethoxy)cyclohexyl]-3-[[2- (difluoromethoxy)pyridin-4-yl]methyl]urea2671-[[2-(difluoromethoxy)pyridin-4-yl]methyl]- 3-[3-(trifluoromethoxy)cyclobutyl]urea2681-[2-(difluoromethoxy)propyl]-3-[[2- (difluoromethoxy)pyridin-4-yl]methyl]urea2691-((1s,3s)-3-fluorocyclobutyl)-3-[[2-(2,2,2- trifluoroethoxy)pyridin-4-yl]methyl]urea2701-(3-chloro-2-fluorophenyl)-3-[1-[2-(difluoro- methoxy)pyridin-4-yl]-2-hydroxyethyl]urea2711-[[2-(difluoromethoxy)pyridin-4-yl]methyl]- 3-[rac-(1R,5S,6R)-3,3-difluoro-6- bicyclo[3.1.0]hexanyl]urea2721-[[2-(difluoromethoxy)pyridin-4-yl]methyl]-3- (2,3,4-trifluorophenyl)urea2731-[[2-(difluoromethoxy)pyridin-4-yl]methyl]-3- [(2S)-1,1,1,4,4,4-hexafluorobutan-2-yl]urea2741-(3,4-difluorophenyl)-3-[[2-(2,2,2-trifluoroethyl) pyridin-4-yl]methyl]urea2751-(3-chlorophenyl)-3-[[2-(2,2,2-trifluoroethyl) pyridin-4-yl]methyl]urea2761-[rac-(1R,3S)-3-(trifluoromethyl)cyclohexyl]-3- [2-(2,2,2-trifluoroethyl)pyridin-4-yl]methyl]urea2771-[[2-(difluoromethoxy)-5-fluoropyridin-4-yl] methyl]-3-[(1r,3r)-3-(trifluoromethyl)cyclo- butyl]urea2781-[1-[2-(difluoromethoxy)pyridin-4-yl]-2- hydroxyethyl]-3-[(3S)-3,4-dihydro-2H-chromen- 3-yl]urea2791-[[6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl] methyl]-3-[(1r,3r)-3-(trifluoromethyl)cyclo butyl]urea2801-[1-[2-(difluoromethoxy)pyridin-4-yl]-2- hydroxyethyl]-3-(3-methylphenyl)urea2811-[[2-(1,1,1-trifluoro-3-methoxypropan-2- yl)oxypyridin-4-yl]methyl]-3-[3-(trifluoro- methyl)cyclobutyl]urea2821-[[6-(difluoromethoxy)pyrimidin-4-yl]methyl]- 3-[(1r,3r)-3-(trifluoromethyl)cyclobutyl]urea2831-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-3-[2- hydroxy-1-[2-(2,2,2-trifluoroethoxy)pyridin-4- yl]ethyl]urea2841-[[2-(2,2,2-trifluoroethoxy)pyridin-4-yl]methyl]- 3-[[1-(trifluoromethyl)cyclopropyl]methyl]urea2851-(1,1,1,3,3,3-hexafluoropropan-2-yl)-3- [[2-(2,2,2-trifluoroethoxy)pyridin-4-yl]methyl]urea2861-[(2R)-1-[2-(difluoromethoxy)pyridin-4-yl]-2- hydroxypropyl]-3-[(1r,3r)-3-(trifluoromethyl) cyclobutyl]urea2871-[(2S)-1-[2-(difluoromethoxy)pyridin-4-yl]-2- hydroxypropyl]-3-[(1r,3r)-3-(trifluoromethyl) cyclobutyl]urea2881-[[2-(difluoromethoxy)pyridin-4-yl]methyl]-3- [(1R,3S)-3-(trifluoromethoxy)cyclopentyl]urea2891-[[2-(difluoromethoxy)pyridin-4-yl]methyl]-3-[2- (3-fluoro-1-bicyclo[1.1.1]pentanyl)-2-hydroxy- ethyl]urea2901-[2-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-2- hydroxyethyl]-3-[[2-(2,2,2-trifluoroethoxy) pyridin-4-yl]methyl]urea2911-[2-(1-bicyclo[1.1.1]pentanyl)-2-hydroxyethyl]- 3-[[2-(difluoromethoxy)pyridin-4-yl]methyl]urea2921-[2-(1-bicyclo[1.1.1 ]pentanyl)-2-hydroxyethyl]- 3-[[2-(2,2,2-trifluoroethoxy)pyridin-4-yl]methyl]urea2931-[(1r,3r)-3-(difluoromethyl)cyclobutyl]-3-[[2- (2,2,2-trifluoroethoxy)pyridin-4-yl]methyl]urea2941-[[2-(difluoromethoxy)pyridin-4-yl]methyl]-3- [(2R)-1,1,1,4,4,4-hexafluorobutan-2-yl]urea55. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11-54, or a pharmaceutical composition according to any one of claims 1-10, wherein R1 is CHF2O— and R6 is substituted with one or two F—.

56. A compound as set out in any one of Tables 1-9 herein or a solvate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound as set out in any one of Tables 1-9 herein or a solvate or a pharmaceutically acceptable salt thereof.

57. A compound of formula (I′) or (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11-56, or a pharmaceutical composition according to any one of claims 1-10 with the proviso that the compound is not one selected from:

58. A compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11-57, wherein such compounds of formula (I) show Kv7.2 EC50<3 μM and selectivity ratio Kv7.3_7.5 / Kv7.2>10×.

59. A pharmaceutical composition according to any one of claims 1-10, or a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof according to any one of claims 11-58, for use in the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2 in a subject in need thereof.

60. A pharmaceutical composition according to any one of claims 1-10, or a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof according to any one of claims 11-58, for use in the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2 in a subject in need thereof, wherein the disorder, disease, or disability is selected from behavioral disorders, mood disorders, neurodevelopmental disorders, intellectual disability, epilepsies, neurodegenerative diseases, pain, migraine, and tinnitus.

61. The pharmaceutical composition for use according to claim 60, wherein the disorder, disease, or disability is a behavioral disorder which is Attention Deficit Hyperactivity Disorder (ADHD).

62. The pharmaceutical composition for use according to claim 60, wherein the disorder, disease, or disability is a mood disorder which is depression.

63. The pharmaceutical composition for use according to claim 60, wherein the disorder, disease, or disability is a neurodevelopment disorder selected from autism spectrum disorder (ASD) and syndromic developmental disorders.

64. The pharmaceutical composition for use according to claim 60, wherein the disorder, disease, or disability is a syndromic developmental disorder selected from Dup15q syndrome (Dup15q), Fragile X syndrome (FXS) and Angelman syndrome.

65. The pharmaceutical composition for use according to claim 60, wherein the disorder, disease, or disability is an epilepsy selected from broad pediatric epilepsy, West syndrome, Ohtahara syndrome, and epileptic encephalopathy.

66. The pharmaceutical composition for use according to claim 60, wherein disorder, disease, or disability is a neurodegenerative disease selected from Alzheimer's disease, and motor neuron diseases.

67. The pharmaceutical composition for use according to any one of claims 59-66, for systemic or local administration such as oral, nasal, parenteral (as by intravenous (both bolus and infusion), intramuscular, or subcutaneous injection), transdermal, vaginal, buccal, rectal, or topical administration modes, intracisternally, intraperitoneally, as an oral or nasal spray, or as a liquid aerosol or dry powder for inhalation.

68. A compound according to any one of claims 11-58, or a pharmaceutical composition according to any one of claims 1-10 for use in therapy.

69. A compound according to any one of claims 11-58, or a pharmaceutical composition according to any one of claims 1-10, or a pharmaceutical composition for use according to any one of claims 59-67, for the manufacture of a medicament for use in the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2.

70. A method for the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2, which method comprises administering a therapeutically effective amount of a compound according to any one of claims 11-58, or a pharmaceutical composition according to any one of claims 1-10, or a pharmaceutical composition for use according to any one of claims 59-67.

71. A kit for use in the therapeutic and / or prophylactic treatment of a disorder, disease, or disability associated with Kv7.2 comprising:a) a compound according to any one of claims 11-58, or a pharmaceutical composition according to any one of claims 1-10, or a pharmaceutical composition for use according to any one of claims 59-67; andb) instructions for use.

72. A process for the preparation of a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11-58, wherein the urea formation comprises the reactions:wherein R1, R2, R3, n, R4, R5 and R6 are as defined herein.

73. A process for the preparation of a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 72, wherein R1 is selected from 7-12 membered heterocycloalkyl, cyano, halogen, haloC1-6alkyl, and 5 membered heteroaryl.

74. A process for the preparation of a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11-58, wherein the process comprises the following reaction step:wherein R1, R2, R3, n, R4, R5 and R6 are as defined herein.

75. A process for the preparation of a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, according to claim 74, wherein R1 is selected from haloC1-6alkoxy, C1-6alkoxy, 4-6 membered heterocyclyloxy, and C3-8cycloalkylC1-6alkoxy and R2 and R3 are hydrogen.

76. A process for the preparation of a compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof, according to any one of claims 11-58, wherein the process comprises the reactions of the following reaction steps:wherein R1, R2, R3, n, R4, R5 and R6 are as defined herein.

77. A process for the preparation of a compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof, according to claim 76, wherein R1 is selected from haloC1-6alkoxy, C1-6alkoxy, 4-6 membered heterocyclyloxy, C3-8cycloalkylC1-6alkoxy, or cyanoC1-6alkoxy, and R2 is hydroxyC1-6alkyl and R3 is hydrogen.

78. A compound of formula (I), or a solvate or a pharmaceutically acceptable salt thereof according to any one of claims 11-58, when manufactured according to a process according to any one of claims 72-77.

71. The invention as hereinbefore described.

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